Chordate Evolution and the Origin of Craniates: an Old Brain in a New Head

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THE ANATOMICAL RECORD (NEW ANAT.) 261:111–125, 2000

FEATURE ARTICLE

Chordate Evolution and the Origin of Craniates: An Old Brain in a New Head

ANN B.BUTLER*

The earliest craniates achieved a unique condition among bilaterally symmetrical animals: they possessed enlarged, elaborated brains with paired sense organs and unique derivatives of neural crest and placodal tissues, including peripheral sensory ganglia, visceral arches, and head skeleton. The craniate sister taxon, cephalochordates, has rostral portions of the neuraxis that are homologous to some of the major divisions of craniate brains. Moreover, recent data indicate that many genes involved in patterning the nervous system are common to all bilaterally symmetrical animals and have been inherited from a common ancestor. Craniates, thus, have an “old” brain in a new head, due to re-expression of these anciently acquired genes. The transition to the craniate brain from a cephalochordate-like ancestral form may have involved a mediolateral shift in expression of the genes that specify nervous system development from various parts of the ectoderm. It is suggested here that the transition was sequential. The ﬁrst step involved the presence of paired, lateral eyes, elaboration of the alar plate, and enhancement of the descending visual pathway to brainstem motor centers. Subsequently, this central visual pathway served as a template for the additional sensory systems that were elaborated and/or augmented with the “bloom” of migratory neural crest and placodes. This model accounts for the marked uniformity of pattern across central sensory pathways and for the lack of any neural crest-placode cranial nerve for either the diencephalon or mesencephalon. Anat Rec (New Anat) 261:111–125, 2000. © 2000 Wiley-Liss, Inc.

KEY WORDS: cephalochordates; arthropods; cerebral vesicle; neural crest; placodes; visual system; cranial nerves; comparative anatomy; evolution

How do highly complex biological and without precedent intermediate structures evolve? Can we conceive of stages? When we examine the wide a series of intermediate stages, each of range of variation across multicellular Dr. Butler has a joint appointment at adaptive value in itself, that could be animals, it is clear that complex bio- George Mason University as Krasnow selected for over generations of organ- Professor of Psychology and Research logical structures have arisen many Professor in the Krasnow Institute for times and, in many cases, seemingly Advanced Study. She received her Ph.D. in anatomy from Case Western Reserve rather suddenly. University in Cleveland, OH, in 1971. She When we examine the A number of recent findings on the previously held faculty positions in the genetic bases for morphogenesis al- Anatomy Departments at George Wash- wide range of variation ington University and Georgetown Uni- low exciting new glimpses into both versity (both in Washington, DC) and across multicellular the embryological development and she subsequently continued her research work in the privately funded animals, it is clear that the evolution of complex structures. Ivory Tower Neurobiology Institute in Eyes, for example, were previously Arlington, VA. Her research interests in- complex biological clude the comparative neuroanatomy of thought by some to have evolved in sensory pathways, particularly of the vi- structures have arisen various taxa many different times in- sual system, in fishes and reptiles; the dependently (Salvini-Plawen and evolution of the telencephalon in ray- many times and, in finned fishes; and the evolution of the Mayr, 1977). From the work of Ge- dorsal thalamus across vertebrates. many cases, seemingly hring and his colleagues (Halder et al., She authored the textbook Comparative 1995), we now know that the same Vertebrate Neuroanatomy (1996, Wiley- rather suddenly. Liss) with William Hodos. single regulatory gene, Pax 6 and its Grant sponsor: National Science Foun- homologues, is responsible for initiat- dation; Grant number IBN-9728155. *Correspondence to: Ann B. Butler, ing the genetic cascade that produces Krasnow Institute for Advanced Study, isms and that would culminate in a a whole eye in vertebrates (lampreys George Mason University, MSN 2A1, complex structure such as an eye or a and jawed vertebrates) and inverte- Fairfax, VA 22030. Fax: 703-533-4325; E-mail: [email protected] brain? Alternatively, how could such a brates (protostomes and nonverte- complex structure appear suddenly brate deuterostomes) alike (see Table

TABLE 1. Useful terms used in discussing comparative neuroanatomy and evolution

Alar plate The dorsal half of the developing neural tube. Arthropod Taxon of animals with segmented bodies and jointed limbs that includes insects and crustaceans. Basal plate The ventral half of the developing neural tube. Bipolar Type of neuron characterized by a cell body with two processes, rather than only one process or more than two processes. In craniates, this type of neuron is sensory and has the cell body located in a ganglion near the central nervous system, into which it projects. Caudal The direction toward or pertaining to the tail of an animal. Cephalopod Taxon of animals with enlarged heads and tentacles that includes octopus and squid. Chordate Taxon of animals wtih a notochord during at least part of the life cycle that comprises urochordates (ascidians), cephalochordates (lancelets), and craniates. Craniate Taxon of animals with migratory neural crest derivatives that comprises myxinoids (hagfishes), petromyzontids (lampreys), and jawed vertebrates. Deuterostome Taxon of metazoa (multicellular animals with more than one type of tissue) in which the anus forms from the blastopore (invagination of the blastula), while the mouth forms from a secondary invagination of the archenteron (primitive gut cavity); comprises echinoderms (starfishes, brittle stars, etc.), hemichordates (acorn worms), and chordates. Dorsal The direction toward or pertaining to the back surface of an animal. Grade A particular level of development or organization shared by a set of species that may or may not be within a single phylogenetic lineage. Multipolar Type of neuron characterized by more than two processes. In craniates, this type of neuron occurs in the brain and spinal cord and also in motor ganglia of the autonomic nervous system. Placode A localized thickened area of epidermis that appears on the surface of an embryo during development. Protostome Taxon of metazoan organisms in which the mouth forms from the anterior part of the blastopore, and the anus forms from the posterior part of the blastopore; includes most invertebrates, such as annelids, arthropods, molluscs, platyhelminthes (including planaria), and nematodes. Pseudounipolar Type of neuron characterized by a cell body with one T-shaped process that develops from a bipolar neuron. In craniates, this type of neuron is sensory and has the cell body in a peripheral ganglion or, in one exceptional case, within the central nervous system. Taxon A group of species at any rank, such as species, class, genus, or family. Ventral The direction toward or pertaining to the belly of an animal. Vertebrate Taxon that comprises petromyzontids (lampreys) and ganthostomes (jawed vertebrates), as the term is used here, or, alternatively, a taxon that also includes hagfishes.

1 for a glossary of terms). The evi- neurogenesis have dramatically al- transition from a cephalochordate- dence is overwhelmingly strong that tered our view of nervous system like common ancestor (Holland et this gene evolved once in the common evolution across animals (Arendt al., 1994; Holland and Graham, ancestor of all bilaterally symmetrical and Nu¨ bler-Jung, 1999). The enigma 1995) to craniates. animals. Modifications have occurred of brain evolution is beginning to This paper reviews some of the re- within the downstream cascade of yield its secrets, and scenarios of cent new findings that illuminate ner- other genes initiated by Pax 6, such how complex brains evolve can be vous system evolution across the ma- that eye spots are produced in plana- envisioned. Some protostomes—ar- jor taxic transitions, with particular ria, ommatidial eyes are produced in thropods and cephalopods in partic- attention to the origin of craniates. the fruit fly Drosophila, cephalopod ular—have complex nervous sys- Major taxic transitions were corre- retinal eyes are produced in cephalo- tems with large brains. Among lated with crucial alterations of early pods, and vertebrate retinal eyes are deuterostomes, craniates likewise developmental events, while at the produced in vertebrates (Halder et al., have large, elaborate brains with di- same time the continuity of most reg- 1995). verse peripheral sensory systems. ulatory genes and morphogenesis of Large brains with elaborate cyto- Craniates also are characterized by a systems was preserved. The key fea- architecture are a second example of unique set of nonneural features. tures of organization across nervous complex biological structures that Comparative analyses of living cra- systems and their surprisingly com- until very recently were thought to niates indicate that the large crani- mon genetic bases are surveyed in se- have evolved independently within ate brain, a host of peripheral sen- lected taxa in this context. The origin various groups of protostomes and sory systems, a cranium, and other of craniates in particular included within craniates (hagfishes and ver- unique craniate features were all multiple seminal changes. The chal- tebrates). As in the case of eyes, re- gained at or about the same time lenge of explicating how these cent new findings on regulatory gene (Northcutt, 1996b; Wicht, 1996; changes all occurred in a mutually expression during the early stages of Wicht and Northcutt, 1998), at the adaptive manner is addressed. FEATURE ARTICLE THE ANATOMICAL RECORD (NEW ANAT.) 113

Figure 1. Schematic, generalized drawings of dorsal views of the brains of (A) an arthropod; (B) a cephalopod; and (C) a craniate. CL, circumesophageal lobes; D, deutocerebrum; FB, forebrain; MB, midbrain; HB, hindbrain; OL, optic lobe; P, protocerebrum; SP, spinal cord; T, tritocerebrum. D: Schematic drawing of a transverse section through the dorsal part of the body of a developing craniate to show the relationships of the alar (A), basal (B), and ﬂoor (F) plates in the neural tube and the positions of the notochord (N), neural crest (NC), overlying ectoderm (E). The neural crest migrates ventrolaterally.

PROTOSTOMES AND (see Brusca and Brusca, 1990). Many studied, the nerve cord has a rostral DEUTEROSTOMES: SAME GENES arthropods, for example, have rostro- specialization: the modestly sized ce- AND SAME BRAINS caudally aligned ganglia called the rebral (or sensory) vesicle of larval as- protocerebrum (which receives visual cidians and lancelets and the large Protostomes comprise a wide array of input from the eyes via large optic brain of craniates. Unlike the situa- taxa including many different groups lobes), the deutocerebrum, and the tion in protostomes, the rostral end of of worm-like organisms, molluscs tritocerebrum. Cephalopod brains the nerve cord does not encircle the (which include cephalopods such as have a large number of circumesopha- gut but instead lies dorsal to it. the octopus and squid), arthropods geal lobes that are individually During embryological development (which include insects), and other di- named, including an extremely large of the craniate brain, the hollow nerve verse groups. Among protostomes pair of optic lobes that receive visual tube comprises a ventrally situated variation in nervous system organiza- input and project into the rostral part tion is extreme. In some protostome basal plate and a dorsally situated alar groups, such as planaria and nema- of the brain. The evolution of these plate (Fig. 1d). The basal plate overlies todes, the nervous system exhibits a collections of ganglia or lobes that can ﬂoor plate cells that play a role in the small degree of rostrocaudal differen- justiﬁably be referred to as brains has dorsoventral patterning of the brain. tiation and mainly comprises two long been thought to have been com- It contains motor neurons and inter- nerve cords that are connected in a pletely independent of brain evolution neurons and gives rise to some of the ladder-like pattern by a series of com- within craniates, due in part to the earliest longitudinal and efferent ax- missures (see Brusca and Brusca, great phylogenetic distance between onal pathways, or scaffolding, of the 1990). In contrast, the nervous system these several groups of bilaterally developing brain (Wilson et al., 1990). has been particularly elaborated in symmetrical animals. The alar plate constitutes the sensory- some protostome taxa, such as arthro- Deuterostomes comprise three ma- receptive part of the nervous system. pods and cephalopods. The rostral jor groups: echinoderms, hemichor- It receives inputs from bipolar sen- components of such elaborated ner- dates, and chordates (Fig. 2). The lat- sory neurons that for most sensory vous systems (Fig. 1a,b) comprise sets ter include craniates and the systems derive from the more laterally of ganglia that encircle the gut in the noncraniate chordates: urochordates, lying neurectoderm, the neural crest, rostral part of the animal. These gan- or ascidians (sea squirts), and cepha- or from placodes—thickened areas of glia receive a variety of afferent sen- lochordates, or lancelets (amphioxus). epidermis (see Northcutt, 1996b). sory inputs, have populations of inter- In deuterostome nervous systems, a Neural crest consists of ectodermal neurons and in some cases cortical- nerve cord is present in the adult cells and initially arises from the re- like cellular architecture, and give rise and/or larval forms. In chordates, gion of the lateral edge of the develop- to efferent motor projection systems which have been most extensively ing neural tube; these cells then mi- 114 THE ANATOMICAL RECORD (NEW ANAT.) FEATURE ARTICLE

Figure 2. Dendrogram illustrating brain evolution in deuterostomes. A: a whole starfish (echinoderm), B: a whole acorn worm (hemichor- date), C: a sagittally sectioned ascidian larva (urochordate), D: a sagittally sectioned lancelet (cephalochordate), and E: a dorsal view of the brain of a lamprey (vertebrate, i.e., representative of craniates) are shown. In the lamprey brain, the rostral expression boundary of Hox-3 is indicated by the dashed line, and the rostral extent of the midbrain is indicated by the paired arrows. C: cerebral vesicle; D: dorsal nerve cord; V: ventral nerve cord. Reproduced from Butler and Hodos (1996) with permission of the publisher. grate laterally and ventrally and cludes some groups of motor neurons. Protostomes contribute neurons to peripheral sen- The hindbrain comprises a rostral me- sory ganglia in both the head and tencephalon (which includes the cer- Recent new findings on protostome body as well as to the peripheral mo- ebellum in jawed vertebrates) and a nervous systems mandate a major re- tor ganglia of the autonomic nervous more caudal myelencephalon, which vision of some of our most fundamen- system. Placodes, which are thickened tal perceptions of nervous system evo- patches of the surface ectoderm, also lution. Until now, it has been widely give rise to many of the neurons in the believed that the elaborated nervous sensory ganglia in the head, just as As humans we systems of arthropods, cephalopods, does the surface ectoderm of both the essentially share the and craniates were evolved com- head and body in protostomes. pletely independently. We are now The craniate brain also has three “same” brain not only confronted with compelling evidence major rostrocaudal divisions: fore- with other primates, that not only the eyes but the whole brain, midbrain, and hindbrain (Fig. nervous system itself is organized in 1c). The forebrain is subdivided into a mammals, and essentially the same way across all bi- rostral telencephalon, which includes craniates but also with laterally symmetrical animals and is the olfactory bulbs, and a more caudal fruit flies and octopuses. specified by the same set of regulatory diencephalon. The latter receives vi- genes during development. As hu- sual input via the optic nerves. It also mans we essentially share the “same” has a visually-related dorsal-most brain not only with other primates, part, the epiphysis, which in verte- is continuous caudally with the spinal mammals, and craniates but also with brates includes the pineal apparatus. cord. Until recently, little if any homo- fruit flies and octopuses. The midbrain is not divided rostro- logue of the craniate brain—a rudi- Arendt and Nu¨ bler-Jung (1999) caudally but has a more dorsal part, mentary hindbrain at best—was be- have recently reviewed these new the tectum, which receives visual and lieved to be present at the rostral end findings in Drosophila and their stun- other sensory inputs, and a more ven- of the nerve cord in any noncraniate ning implications. While some basic tral part, the tegmentum, which in- deuterostome. differences do characterize nervous FEATURE ARTICLE THE ANATOMICAL RECORD (NEW ANAT.) 115 system development in Drosophila umn motor neurons in Drosophila a variety of sensory neurons derived and vertebrates, many similarities in also express other regulatory genes from the surface ectoderm. Long ax- rostrocaudal and mediolateral specifi- that are the same as those expressed onal tracts to coordinate sensory in- cation have been revealed. In Dro- by a population of developing neurons puts with motor outputs would have sophila, the rostral part of the brain— in vertebrates that gives rise to the been present in the central nervous the protocerebrum and part of the neurons of a long central tract, the system, and motor neuronal systems deutocerebrum—is specified by the medial longitudinal fasciculus, and to for effector control of body wall mus- regulatory gene orthodenticle, while branchiomeric motor neurons that in- cles would also have been present. the more caudal part is specified by nervate the muscles of the gill arches. While some of the taxa that evolved Hox genes. This gene expression pat- As Arendt and Nu¨ bler-Jung (1999) subsequent to this common ancestral tern corresponds to that of mammals noted, the chordate branchial appara- form in both the arthropod and crani- and other craniates, where the ortho- tus and its innervation may thus have ate lines, as well as in the cephalopod denticle homologues Otx-1 and Otx-2 arisen from the ancestral body wall line, lacked phenotypic expression of specify the rostral part of the brain— and its central motor control system, these traits, the underlying genetic the forebrain and midbrain—while respectively. Similarly, the craniate bases for their formation were never- Hox genes specify the hindbrain. As neural crest, with its sensory neurons, theless inherited from a common discussed below, these regulatory glia, and numerous other derivatives, ancestor. The brains of fruit flies, genes also identify comparable parts appears to share a lateral column der- octopuses, and humans are not ho- of the cerebral vesicle in ascidian lar- ivation with glial and other elements mologous in the historical sense of vae and lancelets. in protostomes, while the intermedi- phenotypic continuity from a com- As Arendt and Nu¨ bler-Jung (1999) ate column derivatives of various neu- mon ancestor (Wiley, 1980). They are, discussed, the developing brain is also rons in protostomes and the alar plate however, the “same” brains. They are divided into mediolaterally aligned, in craniates are likewise commonly an example of syngeny, sharing the longitudinal columns in both Dro- inherited. same genetic bases that have been in- sophila and vertebrates. Some differ- Most sensory neurons are derived herited with continuity from a com- ences in regulatory gene expression from the surface ectoderm in insects, mon ancestor (Butler and Saidel, occur between these two groups for as Arendt and Nu¨ bler-Jung (1999) also 2000). the medial-most column of midline discussed, and in craniates many of cells, although in both groups these the sensory neurons for the cranial Chordate Origins midline cells serve as inductive cen- nerves of the head region are derived ters for patterning the neurectoderm. from ectodermal placodes (see North- In early development, the process of The latter is divided into three col- cutt, 1996b). These populations of gastrulation involves an invagination umns in both groups—medial, inter- sensory neurons may thus also reflect of the spherical ball of cells that form mediate, and lateral—which are, re- a common heritage. The main differ- the blastula, so that an internal ca- spectively, specified by homologues of ence between arthropods and crani- vity—the archenteron, or primitive the same regulatory genes. The medial ates in terms of the peripheral ner- gut—with an opening, the blastopore, column expresses NK-2/NK-2.2.It vous system would appear to be the is formed. The protostome-deutero- gives rise to the basal plate in verte- derivation of sensory neurons for the stome phylogenetic split involved brates and to interneurons and motor body regions from surface ectoderm changes in the early developmental neurons in Drosophila. In both in arthropods and from neural crest fate of the blastopore. Nielsen (1995) groups, the medial column-derived cells in craniates. As discussed futher postulated that while in the ancestral cells pioneer early axonal scaffolding below, Northcutt and Gans (Northcutt stock of protostomes, the blastopore for long pathways within the develop- and Gans, 1983; Northcutt, 1996b) divided to form both the mouth and ing nervous system. The intermediate recognized the seminal role that mi- the anus, in the deuterostome lineage column expresses ind/Gsh regulatory gratory neural crest tissue played in a new mouth opening was acquried genes in both groups. It gives rise to the origin of craniates. opposite the blastopore, with the lat- the sensory-related alar plate in verte- From the wide array of similarities ter then forming only the anus. Addi- brates and to a variety of cells in Dro- in regulatory gene expression and tionally, a new feeding structure, the sophila, including some motor neu- other related data, a morphotype for ciliary band system, was added and rons. The lateral column expresses the nervous system of the common has been retained in the larval forms msh/Msx. It gives rise to neural crest ancestor of arthropods and craniates of the descendant taxa. The latter lineages, including the sensory bipo- can be deduced (Arendt and Nu¨ bler- structure consists of rows of ciliated, lar neurons and glial cells, in verte- Jung, 1999). This ancestral nervous columnar cells that divide the surface brates and to a variety of glial cells as system would have had a nerve cord of the organism into various domains. well as to some motor neurons in Dro- with a rostral brain that comprised at The beat of the cilia directs food sophila. least a forebrain-midbrain rostral re- particles toward the mouth, and the The fates of the medial-, intermedi- gion, with visual input from paired ciliary band also provides some ate-, and lateral-column components, eyes, and a caudal hindbrain region. structural support for the epithelium while not identical, thus have numer- The hindbrain region and the caudally and for muscle attachment (Lacalli, ous and striking similarities in arthro- extending spinal cord would have re- 1996d). pods and craniates. The medial col- ceived non-visual sensory inputs from With the change to a new mouth, 116 THE ANATOMICAL RECORD (NEW ANAT.) FEATURE ARTICLE the position of the mouth with respect new mouth opening to the arch- opment that is later used by other to the nerve cord shifted (see Arendt enteron (the cavity that will become pathways as they grow and develop and Nu¨ bler-Jung, 1997; Nielsen, the gut) forms as in the chordates (see (Wilson et al., 1990). The initial ax- 1999). The new position of the mouth Nielsen, 1999). Thus, the echinoderms onal scaffolding of vertebrate brains is obviated the need for passage of the and hemichordates exhibit an inter- very similar in pattern to that in in- gut through the nerve cord, and the mediate condition. In chordates, the sects (see Arendt and Nu¨ bler-Jung, anatomical arrangement of ganglia formation of a new anus in addition to 1996; Reichert and Boyan, 1997). Be- encircling the gut as seen in proto- the new deuterostome mouth ac- low, I will discuss the idea that in the stome invertebrates was thereby elim- counts for the perceived dorsoventral ancestral line that gave rise to crani- inated. Arendt and Nu¨ bler-Jung inversion of chordates as compared ates, these basic descending path- (1996) noted a possible comparison of with insects, and the respective nerve ways, along with input from the dien- the preoptic-hypothalamic region and tubes actually occupy comparable po- cephalic visual systems, served as the infundibulum of the brain of verte- sitions. This observation, coupled template for the nonvisual, ascending brates with the stomatogastric ner- with the numerous similarities of reg- sensory systems. vous system (the part of the neuraxis ulatory gene expression during devel- The central nervous system in uro- that surrounds the gut) in arthropods. opment as discussed above, makes a chordate (ascidian) larvae has a so- They suggest that the ancestral new very strong case for the sameness of called sensory vesicle at its rostral chordate mouth would have been lo- the nerve cord across all bilaterally end. The ascidian homologue of cated in this infundibular region of symmetrical animals. orthodenticle, Hroth, is expressed in the nervous system and that a promi- Chordates may have arisen from an the anterior two thirds of the sensory nent set of axons that encircle the sto- ancestral larval form resembling the vesicle (Katsuyama et al., 1996; Wada modaeum anlage in protostomes diplerula larvae of extant echino- et al., 1998). As discussed above, the marks this point. derms and hemichordates, which expression of orthodenticle and its ho- A hypothesis that inversion of the mologues also characterizes the ros- dorsal and ventral surfaces of the tral part of the brain in Drosophila body also occurred in the deutero- and in mammals. Based on the ex- stome line is supported by compelling Chordates may have pression patterns of a number of evidence from gene expression pat- arisen from an ancestral genes, Wada et al. (1998) compared terns during development (see the ascidian sensory vesicle, “neck” re- Nu¨ bler-Jung and Arendt, 1994; larval form resembling gion, and more caudal parts of the Lacalli, 1996a; Arendt and Nu¨ bler- the diplerula larvae of nerve cord to the mouse forebrain, Jung, 1994, 1997), confirming the midbrain, and hindbrain and spinal original, 19th century idea of Geoffroy extant echinoderms and cord, respectively. Other work on St. Hilaire. The gene decapentaplegic hemichordates, which orthodenticle homologues and other is expressed dorsally in Drosophila, gene expression patterns by Williams while its orthologue BMP-4 is ex- have ciliary bands. and Holland (1998) compared the sen- pressed ventrally in vertebrates; thus, sory vesicle to the forebrain and mid- it is expressed on the abneural side of brain of mammals and the neck of the the animal, i.e., opposite to the nerve have ciliary bands. The nerve cord it- ascidian larval nervous system to the cord, in both groups. An antagonistic self formed from fusion and infolding more caudal isthmal region between pair of orthologous genes, short gas- of part of the ciliary band in this an- the midbrain and hindbrain of mam- trulation in Drosophila and chordin in cestral stock (see Nielsen, 1995, 1999; mals. Thus, while the exact correspon- the frog Xenopus, are both expressed Lacalli, 1996d). This idea is consistent dence has not been resolved, there is on the neural side of the animal—ven- with the hypothesis advanced by clear evidence for forebrain vs. hind- tral in insects and dorsal in verte- Garstang at the end of the 19th cen- brain regions of the rostral neural brates. tury, deriving the chordate nerve cord tube in ascidian larvae. Ascidians also While arguments have been made from converged ciliary bands of a exhibit possible precursors of the cra- that this inversion took place at the dipleurula larva. Lacalli (1996d) dem- niate neural crest/or placodal tissues. origin of deuterostomes, Nielsen onstrated how an invagination of the Wada et al. (1998) postulated that the (1999) has more recently proposed ectoderm at the midline between the expression pattern of another pattern- that it occurred at the origin of chor- ciliary bands in a dipleurula larva is ing gene, HrPax-258, indicates that a dates. Nielsen (1999) postulated that a consistent with the process of verte- sensory organ derived from a placode- new anus was also acquired at this brate neurulation, with the ciliated like epidermal thickening in ascidians juncture, accounting for the anatomi- cells of the band becoming incorpo- may be a homologue of the craniate cal relationships of the gut and the rated into the neural tube of a chor- ear. now dorsally positioned nerve cord in date nervous system. Lancelets, the sister group of crani- the chordates. This idea is supported As noted above, longitudinally run- ates, appear to be a fairly close ap- by evidence that in echinoderms and ning axonal pathways, particularly for proximation of the mutual common hemichordates, the blastopore contin- commissural and descending tracts, ancestor (Garcia-Fernańdez and Hol- ues to give rise to the anus, as is the form a basic scaffolding in the early land, 1994; Holland et al., 1994; Hol- general case in protostomes, while a stages of chordate neural tube devel- land and Garcia-Fernańdez, 1996). FEATURE ARTICLE THE ANATOMICAL RECORD (NEW ANAT.) 117

Figure 3. Semischematic drawings of para- sagittal sectins through (A) an early developmental stage of a lancelet and (B,C) a larval lancelet. Rostral is toward the left. Somites numbered 1–9 are shown in A and B, and H3 with arrowhead indicates the rostral boundary of Hox-3 expression. An enlargement of the rostral part of the cerebral vesicle (shaded area), which lies medial to somite 1, is shown in C. Reproduced from Butler and Hodos (1996) with the permission of Wiley- Liss, Inc.

Noncraniate chordates were long ates. The lamellar body, a set of cells sophila. This scenario is also consis- thought to have at most a primordial that produce stacks of membraneous tent with the expression pattern of the hindbrain at the rostral end of their lamellae, appears to be homologous to Distal-less homologue AmphiDll in the central nervous systems. The more the pineal of vertebrates [no epiphy- developing lancelet (N.D. Holland et rostral parts of the chordate neuraxis seal structures have yet been identi- al., 1996). Cells near the anterior end were thought to be unique to crani- fied in hagfishes (see Wicht, 1996)]. A of the neural plate that come to lie in ates, particularly the two major sub- set of infundibular cells appears to be the dorsal part of the neural tube ex- divisions of the forebrain, the telen- homologous to the craniate infundib- press AmphiDll; these and another, cephalon and diencephalon. In larval ulum. Also, a balance organ, which additional group of AmphiDll-express- lancelets, a cerebral vesicle lies at the consists of a small group of ciliated ing cells lie within the anterior three rostral end of the neuraxis, which cor- accessory cells located immediately fourths of the cerebral vesicle. This responds to the ascidian sensory vesi- rostral to the infundibulum, appears finding supports the homology of this cle. to be homologous to part or all of the part of the neural tube to the region of Several structures that lie within hypothalamus of vertebrates (Lacalli Distal-less-related gene expression in the cerebral vesicle have been identi- and Kelly, 2000). the vertebrate forebrain. Also, Am- fied by Lacalli and his co-workers The above comparison of the vari- phiDll is expressed in laterally lying (Lacalli et al.,1994; Lacalli, 1996b,c) ous parts of the cerebral vesicle to the epidermal cells that migrate over the as probable homologues of dience- diencephalon of craniates is highly curling neural plate, suggesting a pos- phalic structures of most craniates corroborated by recent findings on the sible homology of these cells with cra- (Figs. 3, 4). An unpaired frontal organ, expression of the homeobox gene Am- niate neural crest tissue. or eye, is a cluster of pigmented and phiOtx (the lancelet homologue of In the putative lancelet midbrain, associated cells that lies immediately orthodenticle) in this region (Williams Lacalli (1996b,c) described a roof rostral to a neuropore and marks the and Holland, 1996, 1998). The expres- area, or tectum, that contains cells position of the original anterior mar- sion pattern supports homology of the distinctive in their lack of an apical gin of the neural plate. It appears to be region of AmphiOtx expression in the connection to the central canal and a the homologue of the paired, lateral lancelet cerebral vesicle to the fore- ventral part that contains the anterior eyes of craniates. The cells of the fron- brain and midbrain of vertebrates portion of a ventrally lying set of mo- tal eye may include elements homolo- (Simeone et al., 1993) as well as to the tor neurons, the primary motor center gous to both photoreceptors and some sensory vesicle of ascidian larvae and (PMC), that projects to the spinal of the neurons of the retina of crani- the rostral part of the brain in Dro- cord. The latter neurons appear to 118 THE ANATOMICAL RECORD (NEW ANAT.) FEATURE ARTICLE

Figure 4. Semischematic drawing of a dorsolateral view of the anterior end of a 12.5 day lancelet larva, showing the rostral nervous system structures including the frontal organ (eye), infundibular cells, and lamellar body of the cerebral vesicle and the more caudally lying tectum and primary motor center. Reproduced from Lacalli (1996b) with permission of the publisher. correspond to the reticulospinal neu- and that a clear midbrain-hindbrain mologues derived from a lancelet-like rons in the midbrain and hindbrain of boundary is present caudal to the ce- dorsal spinal nerve pattern. craniates (Fritzsch, 1996) and pre- rebral vesicle (Williams and Holland, Lacalli (1996b,c) noted that the sumably are involved in the produc- 1998). frontal eye and its links to the PMC tion of undulatory swimming move- In the head region of lancelets, pe- may be involved in establishing and ments and startle responses (Lacalli, ripherally located sensory cells (Dem- maintaining the orientation that 1996b,c). Lacalli (1996b,c) described ski et al., 1996; Fritzsch, 1996), a pair lancelets assume in the water column three pathways that link the frontal of rostral nerves (Lacalli, 1996b,c), for feeding, maximally shading the eye cells to PMC cells, including a “re- and several small dorsal roots frontal eye, and possibly in increasing ceptor-tectal” pathway from the re- (Fritzsch, 1996; Lacalli et al., 1994) the startle response when illumina- ceptor cells to tectal cells and hence to are present. Fritzsch (1996) found tion changes occur. He postulated PMC cells. that the sensory cells project through that the midbrain may have become In lancelets, the identification of a the first two dorsal sensory nerves into expanded in vertebrates in conjunc- hindbrain region is strongly sup- the anterior part of the neuraxis as far tion with the gain of image-forming ported by the pattern of expression of as the caudal end of the lamellar body, eyes. Lacalli (1996b,c) also stated that Hox genes. The expression of Amphi- i.e., that part of the rostral neuraxis the “expansion of the [vertebrate] Hox3 (Fig. 3), for example (Holland et that has been compared to the hind- forebrain during evolution could have al., 1992), is comparable to the expres- brain region of craniates. He noted involved the stepwise addition of sion of Hox3 in vertebrates (Hunt and that the weight of current evidence blocks of tissue that would resemble Krumlauf, 1991). Considering the ex- favors a hypothesis that the anlagen of segments, without being part of an pression pattern of the Engrailed gene the various sensory organs and cells actual segmental series,” an idea that in lancelets, which extends into the may thicken into placodes and give rise anticipates part of the serial transfor- region of the caudal part of the cere- to sensory receptor and bipolar gan- mation hypothesis presented here. bral vesicle (L.Z. Holland et al., 1996), glion cells in craniates. Likewise, Ro- Fritzsch (1996) posited that the ros- hen-Beard cells and other intramedul- Craniate Brain tral-most motoneurons in the lancelet lary dorsal cells are present in the might be comparable to the trigemi- lancelet spinal cord, pointing to the Each of the three rostrocaudal divi- nal motor neurons of craniates. The presence of nonmigratory neural crest sions of craniate brains—forebrain, weight of the current evidence tissue in cephalochordates (Fritzsch midbrain, and hindbrain—has spe- strongly suggests that the craniate and Northcutt,1993; Fritzsch, 1996). cific cranial nerves that are associated hindbrain is homologous to a region Fritzsch and Northcutt (1993) pro- with it. The motor nuclei for these of the lancelet neural tube caudal to posed that the cranial and spinal nerves lie within the basal plate, and the cerebral vesicle (Holland, 1996) nerves of craniates may be serial ho- sensory nuclei lie within the alar FEATURE ARTICLE THE ANATOMICAL RECORD (NEW ANAT.) 119 plate. As many as twenty-two cranial ganglion cells as Shepherd (1974) nerves are now recognized in most noted—project to the diencephalon aquatic craniates (Butler and Ho- via the olfactory cortex of the telen- dos,1996; Hodos and Butler, 1997). cephalon rather than via the midbrain Three of these cranial nerves have roof. only motor components; these inner- First-order multipolar neurons also vate the extraocular muscles that are constitute the sensory nuclei of other present in lampreys and jawed verte- systems, including the vestibular, gus- brates. Ten have only sensory compo- tatory, and trigeminal (for face and nents, and the remainder have both jaw innervation) systems, as well as sensory and motor components. The pain and temperature-sensing neu- latter mixed nerves innervate the mus- rons within the spinal cord, and have cles of the visceral arches—the man- similar ascending pathways to the di- dibular, facial, and several branchial encephalon, either directly or via the arches of the gill or throat region. midbrain roof. We can thus note that Of the purely sensory nerves, two Figure 5. Schematic, generalized represen- a fundamental principle of craniate are related to the visual system—the tation of a dorsal view of a craniate brain, sensory system design is the contrast optic nerve of the retina and the with rostral toward the top. Two sensory between an extensive diversity of epiphyseal nerve, which originates in ganglia (G) of the peripheral nervous sys- physical stimuli, receptor morphol- tem are shown containing the neuron cell the pineal and/or other epiphyseal body of a sensory bipolar neuron that either ogy, and transduction mechanisms in component in the dorsal midline of has its own sensory-receptive ending, as on the peripheral parts of the systems the diencephalon. The additional sen- the left, or innervates a separate sensory and the remarkable uniformity in the sory cranial nerves include chemical receptor cell (R), as on the right. Each type organization of the central pathways sense nerves for olfaction and taste, of bipolar neuron can give rise to either (see Hodos and Butler, 1997). and/or both of the two types of central the trigeminal nerve for touch and re- pathways illustrated. On the right a path- For most sensory systems in crani- lated modalities of the head, several way that projects from the first-order multi- ates, the bipolar neurons and, where lateral line nerves for electrosensory polar neurons (FOMs) of the alar plate di- present, the specialized receptor cells, and mechanosensory modalities, and rectly to the diencephalon (D) is illustrated. are both derived from migratory neu- On the left a pathway that projects from the the vestibulocochlear (statoacoustic) FOMs to the diencephalon via a relay in the ral crest and/or placodes (see North- nerve for balance and hearing senses. midbrain (M) is indicated. In all cases, the cutt, 1996b). A major advance in un- The full set of cranial nerves—both diencephalic alar plate neurons, in turn, derstanding the evolution of the motor and sensory—are comple- project to the telencephalon (T). nervous system and other major mented by a series of segmental spinal structures unique to craniates was nerves that supply touch and related the bipolar neuron inputs are the first made by Northcutt and Gans (see sensory modalities as well as efferent multipolar neurons in the sensory Northcutt and Gans, 1983; Northcutt, motor innervation for the body. pathway and are thus referred to here 1996b) with their insights on the ori- The receptors for the various sen- as first-order multipolar neurons,or gin and role of migratory neural crest sory nerves of the head and body are FOMs. and placodes in the transformation to diverse in their structure and their Most sets of FOMs project via one the craniate grade. Based on findings transduction mechanisms. This pe- or two pathway formats—either di- by a number of workers, they recog- ripheral diversity contrasts with the rectly to various parts of the dienceph- nized that most of the tissues of the striking similarity in the basic organi- alon and/or to the diencephalon via a head that were newly acquired by the zation of the central multisynaptic synaptic relay in the midbrain tectum. first craniates arise embryologically sensory pathways. As modified from For example, the visual system bipo- from migratory neural crest and/or an original idea of Shepherd (1974) lar neurons project to retinal ganglion placodes, including special sense or- that compared olfactory and visual cells, which are the FOMs of this sys- gans, the lens of the eye, and the bi- pathways, similar organization of tem. The retinal ganglion cells then polar (including pseudounipolar) neu- central pathways (Fig. 5) can be rec- project to the diencephalon directly rons of nonvisual cranial nerve ognized across all craniate sensory and also project to it via the roof of the ganglia and spinal nerve ganglia. The systems (see Butler and Hodos, 1996; midbrain. Likewise in the somatosen- special sense organs include the audi- Hodos and Butler, 1997). The similar- sory system, the bipolar dorsal root tory, vestibular, and lateral line recep- ity begins with the bipolar (or ganglion cells project to their FOMs, tors, while the bipolar sensory neu- pseudounipolar) element in the neu- the dorsal column nuclei, which in rons include the bipolar receptor cells ronal chain, whether or not the recep- turn project to the diencephalon di- for the olfactory and somatosensory tor element is separate from it. In all rectly and also via the roof of the mid- systems, with their distally-modified sensory systems, the bipolar neurons brain. In the auditory and lateral line receptor endings, as well as the bipo- terminate on groups of multipolar systems, only midbrain roof pathways lar neurons of the sensory ganglia of neurons within the central nervous to the diencephalon are present. The the auditory, vestibular, and lateral system that in turn project to other olfactory system differs in one regard: line systems. Among non-visual recep- groups of multipolar neurons. The the mitral cells that constitute its tor cells, only the taste buds do not various groups of neurons that receive FOMs—comparable to the retinal arise from migratory neural crest or 120 THE ANATOMICAL RECORD (NEW ANAT.) FEATURE ARTICLE placodes but instead simply arise bilaterally symmetrical animals, such sider is how an organism could derive from the oral endoderm (see North- as arthropods and cephalopods. any benefit from the elaboration of its cutt, 1996b). Northcutt and Gans The single seminal change in ner- brain in the absence of any peripheral (1983) identified the gain of migratory vous system evolution that occurred nervous system with afferent sensory neural crest and placodes as a fun- at the origin of craniates and that can inputs. This question easily yields an damental and crucial evolutionary now be identified as new was the der- answer. The elaboration of the brain change that occurred at the origin of ivation of most of the sensory compo- across bilaterally symmetrical ani- craniates. nents of the peripheral nervous sys- mals often includes elaboration of From comparative analyses of cra- tem from migratory neural crest and paired, enlarged eyes. In craniates, the niate brains, a morphotype of the thickened ectodermal placodes, retinas of the lateral eyes derive from brain in the earliest craniate stock can rather than from general ectoderm. As the diencephalon1 itself rather than be constructed (Wicht and Northcutt, Northcutt and Gans (1983) realized, from neural crest or placodes, or from 1998; Wicht; 1996). In marked con- the new head achieved with the gain surface ectoderm as in Drosophila (see trast to cephalochordates, the ances- of migratory neural crest and pla- Halder et al., 1995). An elaborated vi- tral craniate morphytype had a pleth- codes was, indeed, the craniate hall- sual system with descending path- ora of unique features, which mark, allowing the gain of the crani- ways to motor neuronal pools in the included a telencephalon with pallial ate type of peripheral nervous system hindbrain could bestow a major selec- and subpallial parts, paired olfactory along with the plethora of other deriv- tive advantage for an organism that bulbs with substantial projections to atives of the migratory neural crest. was not yet a craniate but profoundly most or all of the telencephalic pal- The latter include large parts of the different from its immediate cephalo- lium, paired lateral eyes and ears, a skull, the sensory capsules, branchial chordate-like predecessor. lateral line system for both electrore- bars, chromaffin cells, melanocytes, As Holland and Graham (1995) dis- ception and mechanoreception, spinal and muscle of the aortic arches (see cuss, antagonism between a medially cord dorsal root ganglia, and an auto- Northcutt, 1996b). Thus, craniates expressed, neural-inducing factor and nomic nervous system. In addition to have an “old” brain in a new head. a more laterally expressed, neural-re- ascending sensory pathways as dis- pressing factor could have resulted in cussed above, descending, motor-re- CRANIATE TRANSITION: the formation of a neural plate and its lated pathways from various fore- CONCURRENT GAIN OR SERIAL derivatives in the ancestral line of brain and midbrain areas were chordates. A small shift in the medio- TRANSFORMATION? present. Comparison with cephalo- lateral gradient of this expression pat- chordates (Lacalli, 1996b,c) suggests The transition to the new craniate tern might account for a serial trans- that the ancestral craniates also pos- head was indeed a sudden event of formation of the nervous system sessed a median epiphysis even considerable complexity. Whether within the ancestral craniate lineage. though extant hagfishes lack this this event occurred simultaneously Essentially, taking extant cephalo- structure (see Wicht, 1996). with the elaboration of the brain is a chordates as an approximate ances- The many new features and exten- question that has been little explored tral model for craniates (Fig. 6A), I sive central pathways that constitute in the literature to date. That these the craniate brain morphotype were two events were at least approxi- acquired from a common ancestor mately concurrent (Holland and Gra- 1The term diencephalon as used here shared with cephalochordates and re- ham, 1995) is a reasonable deduction. includes the region identified as the sembling extant cephalochordates in Northcutt (1996b) proposed that the ventral part of the secondary prosen- many if not all features. The brain of origin of craniates was rapid and cephalon by Puelles and Rubenstein ancesral craniates was newly elabo- “without transitional forms.” One (1993), which predominantly com- rated, i.e., expanded and composed of must indeed ask how an organism prises the hypothalamus and also multiple new cell types and neuronal could derive any benefit from the gain gives rise to the eye stalks and the groups, but noncraniate chordates of a peripheral sensory nervous sys- developing retinas. It is of note that in have clearly homologous major divi- tem without the capacity to also gen- their prosomeric model of brain de- sions—including the diencephalon erate the central nervous system cell velopment in mammals, the eye stalk with both retinal and pineal visual groups and pathways that process the forms at the rostral-most part of the systems, a putative midbrain region, afferent information. neuraxis except for the overlying tel- and a hindbrain—and protostomes An explication of how these two encephalon. Comparably in lancelets, have similar forebrain/midbrain and events could have been linked and oc- as discussed in the text, the frontal hindbrain divisions under the same curred simultaneously has not been organ, or eye, is located at the rostral- regulatory gene control. Thus, we now offered, however. The regulatory most limit of the neuraxis (Lacalli, realize that most of the brain per se genes that specify the central nervous 1996b,c), and a region that appears to was not “new” in craniates. It was, in system are different from those that be homologous to at least part of the fact, not only shared with other chor- specify the periphery and cannot be craniate hypothalamus is present ven- dates but also precedented by the assumed to have upregulated as a tral to this frontal organ (Lacalli and brains achieved in other radiations of unit. The alternative question to con- Kelly, 2000). FEATURE ARTICLE THE ANATOMICAL RECORD (NEW ANAT.) 121

Figure 6. Lateral, schematic, generalized views, using the conventions of Walker and Liem (1994), of the rostral part of the body of (A) a hypothetical cephalochordate as a model of the common ancestor of modern lancelets and craniates; (B) a transitional “cephalate” with elaboration of paired eyes and the alar plate regions of the diencephalon and mesencephalon; and (C) a developing, extant craniate, with the addition of the telencephalon and craniate- type neural crest-placode peripheral sensory systems and other neural crest derivatives. In the hypothetical common ancestral cephalochordate, the notochord does not extend as far rostrally as in extant lancelets, based on comparison with the condition of the notochord in extant ascidian larvae; in all cases shown here, the notochord does not extend rostrally beyond the approximate midbrain-forebrain border. AV, craniate auditory-vestibular organ; BO, balance organ; DRG, dorsal root ganglion; Ey, lateral eye; Ep, epiphysis; FO, frontal organ; G, gill slit; H, hindbrain; Hy, hypothalamus; LB, lamellar body; M, midbrain; Mo, mouth; N, notochord; NC, nerve cord; O, olfactory organ; OB, olfactory bulb; OH, oral hood; P, pharynx; PS, pharynx with pharyngeal slits; PMC, primary motor center; SC, spinal cord; T, tectum; Tel, telencephalon. propose that an initial transition oc- sory neurons would also have been Evidence for Serial curred to a grade roughly approxi- present. This “cephalate” condition Transformation mating an insect or cephalopod would then have made the further brain in a noncraniate chordate transition to the craniate grade (Fig. First, a simple observation is telling. body—a creature that one might call 6C) with the bloom of the migratory Elaborated brains with paired eyes a “cephalate” (Fig. 6B). This stage neural crest and ectodermal, neuro- have occurred multiple times across would have had an elaborated alar genic placodes. This model of a se- bilaterally symmetrical animals, while plate such that the diencephalon rial transformation is an extension the craniate-type of migratory neural would have been enlarged, and the of the conclusions of N.D. Holland et crest and ectodermal placodes has oc- paired eyes would form as evagina- al. (1996) and of Williams and Hol- curred only once. While invertebates tions from it. The alar plate of the land (1996), who postulated that “a clearly have precursors of the latter midbrain roof would likewise have distinct differentiated forebrain tissues, the elaboration of them into been enlarged to form a definitive evolved before the separation of the craniate-type of peripheral ner- midbrain, and existing descending cephalochordates and vertebrates, vous system with sensory nerve gan- visual pathways to motor centers of predating skeletal tissues, migratory glia and into multiple new nonneural the midbrain and hindbrain would neural crest and elaboration of the tissues is unique to craniates. Thus, have been expanded upon. Lesser in- vertebrate genome,” and it is based elaborated brains with paired eyes, puts from epidermally-derived sen- on several lines of evidence. specified by the same set of regulatory 122 THE ANATOMICAL RECORD (NEW ANAT.) FEATURE ARTICLE genes, can occur without the elabora- self gives rise to the retina, dorsal and more “medially restricted” nervous tion of craniate-type neural crest and ventral thalamus, hypothalamus, and system, as in lancelets and insects, or placodes. Also of note, the converse most of the rest of the brainstem. As a more “laterally expansive” one, with condition—elaboration of neural Northcutt (1996b) discussed, the parts the addition of the craniate-type of crest and placodes absent an elabo- of the vertebrate brain that are derived elaboration of migratory neural crest rated brain with paired eyes–has from the longitudinal and transverse and placodes. As Northcutt (1996b) never been documented. Second, an neural folds, including the telencepha- has noted, small alterations in medio- equally fundamental observation is lon, may be uniquely derived in crani- lateral transduction events during that in craniates, no populations of ates. In contrast, the neural plate gives neurulation may have been of crucial first-order multipolar neurons that re- rise to most of the diencephalon with significance for craniate evolution. ceive input from neural crest/placode- the paired eyes as well as to most of the Finally, evidence from regulatory derived sensory systems exist in the midbrain, hindbrain and spinal cord— gene expression studies allows for a diencephalon or midbrain (see Butler structures that have syngenogues common cephalochordate-craniate and Hodos, 1996). This absence is re- (corresponding structures with the ancestor with either paired lateral markable in that such peripheral ner- same genetic specification) in insects eyes or a single, medial eye, as in ex- vous system sensory systems occur and homologues in lancelets. tant lancelets. A notochord product throughout all other levels of the A transitional form that preceeded that is produced by the floor-plate neuraxis: telencephalon, hindbrain, craniates thus could have elaborated cells of the neural plate due to the and spinal cord. This difference al- the neural plate tissue, similar to expression of the gene sonic hedgehog lows for the possibility that the retinal brain development in insects for ex- (Shh) contributes to the dorsoventral ganglion cells, the FOMs of the paired ample, without elaborating the more differentiation of alar and basal plates eye visual system, were established and is also involved in the develop- prior to the gain of the craniate-type ment of the paired eyes (see Ruben- of peripheral nervous system. When Evidence from stein and Beachy, 1998; Rubenstein et the latter arrived, the diencephalic al., 1998). While the homeobox gene and mesencephalic alar plate capacity regulatory gene Pax 6 functions as a master regulator to form FOMs was already spoken for expression studies gene for initiating eye formation, as by the visual system, resulting in the discussed above, interruption of the formation of FOM sites for the neural allows for a common Shh signal results in the production of crest/placodally-derived systems only cephalochordate- a single, median, cyclopic eye (Chiang in the rest of the neuraxis. et al., 1996). As Lacalli (1994) has Third, during development in crani- craniate ancestor with pointed out, while the frontal organ, ates, the neural plate and the neural either paired lateral or eye (which incorporated the apical folds give rise to different structures. eyes or a single, medial organ of nonchordate deuterostomes) As Northcutt (1996b) has discussed, is unpaired in lancelets, instances of differences in neurulation between eye, as in extant both single and paried apical organs lancelets and craniates may account lancelets. occur across various species of echi- for the major differences in both alar noderm larvae, and the latter develop plate and neural crest and placode de- by an initial midline outgrowth fol- rivatives in these groups. In lancelets, lowed by a splitting process, as is the the neural plate overgrows to form the laterally lying ectodermal region that case for the paired eyes of vertebrates. neural tube without folding of the tis- forms the neural fold tissue in devel- Thus, paired eyes could already have sue along the border of the neural oping craniates. The known underly- been present in the common ancestor plate with the adjoining epidermis. In ing contributions of regulatory genes of extant cephalochordates and crani- contrast, vertebrate gastrulation is to the formation of the neural plate ates. characterized by the formation of and related structures (see Lumsden double-walled neural folds at the lat- and Krumlauf, 1996; Kerszberg and Implications for Craniate eral and anterior aspects of the neural Changeux, 1998; Rubenstein et al., Evolution plate; the inner walls of these longitu- 1998) allow for this possibility. Ini- dinal and transverse neural folds give tially, neural tissue development is an- A serial transformation scenario has rise to portions of the alar plate as tagonized by a repressive influence of several fundamental implications for well as to neural crest cells, while the bone morphogenetic proteins (BMPs), brain evolution in craniates. One such lateral walls of these folds give rise to which promote epidermal fate. In the implication is that elaboration of vi- part of the cephalic epidermis and to medial region that will give rise to the sual system pathways previous to the placodes. As demonstrated by Eagle- neural plate, BMPs are inhibited by elaboration of the neural crest-pla- son and Harris (1990), the alar plate the expression of chordin, which is codal peripheral nervous system components derived from the neural produced by cells in the underlying would account for the uniformity of folds include most if not all of the notochord, allowing the formation of central sensory pathways. The scaf- telencephalon and, more caudally, the neural plate. An alteration of the folding provided by descending visual parts of the brainstem and most of the mediolateral interaction of BMPs and system pathways—from diencephalon cerebellum, while the neural plate it- chordin could thus contribute to a to midbrain to motor neuronal FEATURE ARTICLE THE ANATOMICAL RECORD (NEW ANAT.) 123

Figure 7. Schematic diagrams of known visual system connections in the (A) the lancelet brain with a descending visual pathway; (B) the hypothesized “cephalate” brain representing the ancestral cephalochordate-craniate transitional condition; and (C) extant craniates. In the “cephalate” brain, paired eyes are present, and the descending visual system pathway via the diencephalon and midbrain tectum is augmented, while in extant craniates the telencephalon (pallium and striatum) is added with afferent input from the diencephalon, and additional, craniate-type, neural crest-placode, sensory pathways are added that use the same alar-plate template as the descending visual pathways. mNC/P, migratory neural crest and placodes; PMC, primary motor center. pools—could have served as a tem- 1988) and in frogs (Neary and Wilc- produce sensory-receptive neuronal plate for the patterning of the ascend- zynski, 1979, 1980). A subsequent pools. This capacity extends along the ing pathways of the neural crest-pla- gain of the telencephalon and other entire rostrocaudal extent of the alar code systems (Fig. 7). For most of structures derived from the neural plate and was of fundamental impor- these pathways, the various sets of folds and the elaboration of migratory tance for the transition to craniates. FOMs are located in the hindbrain neural crest and placodes (see North- The bipolar sensory neurons derived and spinal cord rather than in the di- cutt, 1996a,b) would have then pro- from migratory neural crest and pla- encephalon, and their projections to vided the ultimate rostral destination codes in craniates might not qualify as the midbrain and diencephalon are for sensory projection systems (see serial homologues of retinal bipolar thus regarded as “ascending.” Fig. 7) that were already established neurons, due to the significant latero- Lancelets have only a descending vi- via the visual system to the penulti- medial difference in their ectodermal sual pathway, from the diencephalic mate site of the diencephalon. derivation. On the other hand, one frontal eye to the midbrain tectum The second implication involves ho- can deduce that the FOMs for the neu- and, via the PMC, to the spinal cord mology of the various populations of ral crest/placode sensory systems are (Lacalli, 1996b,c). Such descending alar plate first-order multipolar neu- serial homologues of the retinal gan- pathways are also present in some ex- rons. FOM-type circuits predate cra- glion cells: all of these FOMs are alar tant craniates: for example, within the niates. They can be identified in lance- plate, sensory-receptive neuronal pop- diencephalon, the anterior nucleus of lets (Lacalli, 1996b) and arguably in ulations that have the capacity to be the dorsal thalamus and some of the various invertebrates. They represent generated and/or maintained given pretectal nuclei project to the mid- a basic capacity of the chordate alar the presence of the sensory input. brain optic tectum in some teleost plate and comparable central nervous That the craniate central nervous fishes (Northcutt and Wullimann, tissue in nonchordate invertebrates to system has the potential to generate 124 THE ANATOMICAL RECORD (NEW ANAT.) FEATURE ARTICLE and/or maintain several sets of alar The fourth grade adds neural fold de- Arendt D, Nu¨ bler-Jung K. 1996. Common plate, multipolar neurons to form an rivatives. In the second and perhaps ground plans in early brain development even the first of these grades, the fun- in mice and flies. BioEssays 18:255–259. ascending sensory pathway for a new Arendt D, Nu¨ bler-Jung K. 1997. Dorsal or set of ingrowing bipolar sensory ax- damental rostrocaudal divisions of ventral: similarities in fate maps and ons is elegantly demonstrated by the the central nervous system are estab- gastrulation patterns in annelids, arthro- electrosensory lateral line system of lished, with the diencephalon being pods and chordates. Mech Dev 61:7–21. fishes. Despite phenotypically inde- the most rostral division and the sen- Arendt D, Nu¨ bler-Jung K. 1999. Compari- sory neurons predominantly derived son of early nerve cord development in pendent evolution of electroreceptors insects and vertebrates. Development and their afferent bipolar neurons and from simple surface ectoderm. In the 126:2309–2325. receptors at least several times among arthropod-cephalopod grade, the cen- Brusca RC, Brusca GJ. 1990. Invertebrates. teleosts (Bullock et al., 1983), the central nervous system is enlarged and Sunderland, MA: Sinauer Associates, tral FOM target in these fishes–the elaborated, and paired eyes are Inc. present. In the craniate grade, the mi- Bullock TH, Bodznick DA, Northcutt RG. electrosensory lateral line lobe—is 1983. The phylogenetic distribution of similar in its position in the brainstem gratory neural crest/placodally-de- electroreception: evidence for conver- and in its ascending projections to the rived peripheral nervous system with gent evolution of a primitive vertebrate diencephalon via the midbrain roof. its sensory ganglia blooms, and the sense modality. Brain Res Rev 6:25–46. Further, these pathways mimic the telencephalon, some components of Butler AB, Hodos W. 1996. Comparative vertebrate neuroanatomy: Evolution and corresponding electrosensory path- the brainstem, and nonneural migra- adaptation. New York:Wiley-Liss. way in cartilaginous fishes (see Butler tory neural crest derivatives are Butler AB, Saidel WM. 2000. Defining and Hodos, 1996). The FOMs in each added. At least in these respects, the sameness: historical, biological, and gen- case project rostrally to the dienceph- transition of the nervous system from erative homology. BioEssays (in press). alon via a relay in the midbrain (and the cephalochordate grade to the cra- Chiang C, Litingtung Y, Lee E, Young KE, niate grade may have involved a serial Corden JL, Westphal H, Beachy PA. from the diencephalon to the telen- 1996. Cyclopia and defective axial pat- cephalon), just as auditory and other transformation through the arthro- terning in mice lacking Sonic hedgehog midbrain-relayed sensory systems do pod-cephalopod grade. gene function. Nature 383:407–413. (see Hodos and Butler, 1997). In the Demski LS, Beaver JA, Morrill JB. 1996. many fishes that are not electrorecep- ACKNOWLEDGMENTS The cutaneous innervation of amphioxus: a review incorporating new obser- tive, no corresponding set of central I am very grateful to Shaun Collin and vations with DiI tracing and scanning cell groups is present. The similarity Justin Marshall for inviting me to at- electron microscopy. Israel J Zool 42:S- of pattern for “new” central pathways 117–S-129. tend their 1st International Confer- is exhibited for other modalities as Eagleson GW, Harris WA. 1990. Mapping ence on Sensory Processing of the well, such as in the unique trigeminal of the presumptive brain regions in the Aquatic Environment, Heron Island, neural plate of Xenopus laevis. J Neuro- pathway that is present in infrared- Australia, in March, 1999, where my biol 28:146–158. detecting snakes (see Hodos and But- ideas discussed herein were first artic- Fritzsch B. 1996. Similarities and differ- ler, 1997). A possible explanation for ences in lancelet and craniate nervous ulated, and I thank the other confer- being able to add on an additional systems. Israel J Zool 42: S-147–S-160. ence attendees in general and William sensory system in the same pattern as Fritzsch B, Northcutt RG. 1993. Cranial Saidel in particular for their helpful other sensory systems, i.e., serially ho- and spinal nerve organization in am- and encouraging feedback. I thank phioxus and lampreys: evidence for an mologous, alar plate FOMs projecting Thurston Lacalli for his kind gift of ancestral craniate pattern. Acta Anat to their own midbrain and dience- 148:96–109. the drawing for Figure 4 and for his phalic targets, derives from postulat- Garcia-Ferna`ndez J, Holland PWH. 1994. many and detailed comments and ing use of the same template estab- Archetypal organization of the am- suggestions on the manuscript, which lished by the original visual system phioxus Hox gene cluster. Nature 370: were of considerable help. I thank 563–566. pathways. Kelly Cookson for producing Figure 7 Halder G, Callaerts P, Gehring WJ. 1995. The third implication is that a sim- and for assistance with graphics work New perspectives on eye evolution. Curr ple mediolateral shift in BMP/chordin Opin Genet Dev 5:602–609. for several other figures. The com- expression can significantly contrib- Hodos W, Butler AB. 1997. Evolution of ments and suggestions of the two ute to the specification of nervous sys- sensory pathways in vertebrates. Brain anonymous reviewers were of consid- Behav Evol 50:189–197. tem morphology across all bilaterally erable help, and the manuscript ben- Holland LZ, Holland PWH, Holland ND. symmetrical animals. Such a shift efited substantially thanks to their 1996 Revealing homologies between could successively produce nervous body parts of distantly related animals careful and thorough reviews. I also systems of the planarian-nematode by in situ hybridization to developmen- express my gratitude to Dr. James grade, the cephalochordate grade, the tal genes: amphioxus vs. vertebrates. In: Olds, Director of the Krasnow Insti- Ferraris JD, Palumbi SR, editors. Molec- arthropod-cephalopod grade, and the tute for Advanced Study, for his sup- ular zoology: advances, strategies, and craniate grade. In the first of these port of all my efforts and his particu- protocols. New York: John Wiley, p 267– grades, the nervous system is derived 282. lar encouragement in this endeavor. from the epidermis (see Brusca and Holland ND, Panganiban G, Henyey EL, Brusca, 1990). In the second and third Holland LZ. 1996. Sequence and devel- LITERATURE CITED opmental expression of AmphiDll,an grades, its components appear to cor- amphioxus Distal-less gene transcribed respond to the neural plate-deriva- Arendt D, Nu¨ bler-Jung K. 1994. 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