Some Aspects of Developmental Neurology: a Review SAMUELP

Some Aspects of Developmental Neurology: A Review SAMUELP. HICKS

(New England Deaconess Hospital and Harrard Medical School, Boston, Mass.)

The increasing interest in the ontogenetic and with in basic physics and chemistry. ... As we genetic aspects of abnormal development and neo now view it, development is an assembly-line plasia in the nervous system makes a presentation process in which countless component events are of some aspects of neuroembryology timely. Seem brought together in orderly patterns in regular ingly unrelated medical problems of growth are succession and are interwoven with one another by coming more and more to have a common meeting innumerable specific interactions." ground in basic fields of developmental biology. What are some of these engineering perform In medical practice, for example, a newborn anen- ances, and what lies behind them? In the present cephalic monster, an idiot child who excretes phen- state of our knowledge, with its numerous gaps, we ylpyruvic acid in its urine, a young adult with a are still at the stage of studying the component retinoblastoma, and a victim of an hereditary events and describing the parts that go into what ataxia might seem to have nothing in common but we see as morphogenesis. We are a long way from simply to be the result of "environmental acci Weiss' ideal of understanding the assembly process dents." Actually, these are no accidents but repre as a whole, but a number of areas have been of sent specific problems in development, with a especial interest to experimental embryologists, promise of real answers. These particular abnor biochemists, anatomists, and geneticists. Some of malities have a certain inevitableness now, because these may be enumerated. One concerns the prob their origin can be traced back to the primary lem of how the nervous system makes its first genetic material in the germ cells; but progress is appearanceâ€”-the so-called induction of the nerv being made toward a better understanding of the ous system. The means by which one group of steps that lie between a peculiar chromosome con cells "induces" another group to differentiate is a figuration and such deviations from normal ontog major problem, not only in the inception of the eny. When those steps are understood, prevention neural plate but as a basic phenomenon through may be possible. out embryogenesis. Another area is the study of The study of how the nervous system may de the mechanics by which cells that make up the velop abnormally must be based on a knowledge nervous system originate, differentiate, migrate, of its normal embryology, for what we call abnor aggregate, and interconnect to form the complex malities are really variations or deviations from functioning organization that we know as the normal or average pathways of development. A nervous system. During ontogeny each neuron primary goal in any such study is to learn how the acquires a biochemical submicroscopic specificity nervous system functions and what things disturb that makes almost every nerve cell different from it. The foundation for this is how it was put to every other, and the relation of this to integrated gether in the first place, since morphogenesis de behavior has been much studied. How the genie termines the structural basis of function. The material at the beginning of development trans morphogenesis of the nervous system is compli lates itself into the specific form and function of a cated, and it cannot, unfortunately, be reduced to mature organism is receiving increased attention only a few simple laws based on physical chemis from multiple disciplines. The impact of embry try or enzyme action. Actually, there is a great ology has been more superficial in oncology, but deal more to the problem. Weiss (1950) has empha some interrelations have attracted interest. sized this by saying that "The complex engineer This review will tell about some of the work go ing performances of technology are a much more ing on in the areas just enumerated, and emphasis pertinent model of the nature of morphogenesis will be on early morphogenesis. This can perhaps than are the more elementary phenomena dealt be done best by first refreshing the reader's mind * Some of the work referred to is supported by AEC Con about how animals with backbones develop, then tracts AT (30-1) 901 and 1452, USPHS Grant B382, and UCP going on into the subjects of neural induction, how Research and Educational Foundation. the components of the nervous system are put to Received for publication December 22, 1956. gether, the early development of functional specific- 251

ity, genetic and chromosomal aspects, and finally blastic and a hypoblastic layer. Above this is the a brief reference to neoplasia. The available data amniotic sac, below the yolk sac. Mesoderm forms are by no means sufficient to form a smooth ac at the disc rim and gradually forms a middle count of the origin of the nervous system at pres "germ layer" by the time that a primitive streak ent, and they can only suggest some of the mech forms. A mesodermal node forms in the streak and anisms by which its development goes awry. apparently by gastrulation forms the prechordal and chordal mesoderm whose importance will be VERTEBRATEDEVELOPMENT discussed. The lateral mesoderm is not believed to The earliest vertebrates perhaps had simply an flow into the streak to become redistributed by elementary receptor-effector neural axis. During gastrulation. evolution there was added a variety of increasingly These vertebrates have arrived by different complex associative and information-storing de paths at a stage where mesoderm underlies ecto vices that integrated and modified neural function derm. The mesoderm is essential to the transfor in adaptation to surroundings. Despite the great mation, or induction, of the ectoderm into neurec- array and different complexities of present-day toderm, which forms the nervous system. With vertebrate nervous systems, there are common mammals used now as examples of further devel features in their development (9, 12, 18, 48, 49, opment, the transformed central ectoderm, now a 54, 55, 65, 66, 72). neural plate, broadens anteriorly to be shaped like Following fertilization (or parthenogenesis) and a long blunt triangle. Caudally the plate lengthens various patterns of cleavage, the vertebrate cell but is narrower. The anterior brain-to-be grows mass comes to a stage called a blÃ¡stula in which laterally, the edges curl up and inward, and the the beginnings of what we arbitrarily call an em caudal spinal cord-to-be does the same on a bryo first appear (63, 67, 84, 95, 104, 115). A proc smaller scale. Both close medially to form the ess called gastrulation ("forming a little stomach") neural tube, enlarged anteriorly. By the time the occurs in which relatively â€¢¿undifferentiatedcells lateral folds have become well developed the an actively migrate and stream into certain relative terior end is bent ventrally over the early heart positions that give rise to a "layered" early em and gut structures, and the optic pits are recog bryo. The amphibian blÃ¡stula is a hollow sphere nizable ventrolaterally. At about the 20-somite of cells with a thin roof and a thick yolk-cell floor. stage in the rat and at about the same in man, An indentation on the upper surface appears, in- cerebral vesicles are becoming evident as bulges vaginates, and outer cells stream toward and into of the anterior neural tube, and the neuraxis may this opening (blastopore) to underlie cells on the be arbitrarily divided into forebrain, in-between- outside and form by their relative positions the brain (diencephalon), midbrain, hindbrain, and so-called germ layers. The relations are so rapidly spinal cord. Subsequent growth involves a com changing that in point of time ectoderm, ento- plex sequence of gross flexures and disproportion derm, and mesoderm are very arbitrary terms ate growths. The cerebral vesicles with their ven- applied to the layers. In the bird the blÃ¡stulaforms trolateral striatal masses bulging into the ven a disc, instead of a vesicle, on a sea of yolk, and tricles increase greatly in size. The thalamic struc during gastrulation cells stream toward and into tures develop medially in the diencephalic region, a groove in the primitive streak, a central concen and the cerebellum arises from the anterior part of tration of cells in the disc. The rat and man, be the rhomboid flexure of the medulla still later on cause of placentation, are somewhat more com (see Chart 1). plex. The hollow blÃ¡stulaof the rat develops a cell At the cellular level, the early nervous system mass at one pole, the outer part of which becomes derives from the primitive neural plate, a layer of ectoplacenta. The inner part of the cell mass forms proliferating cells. Similar cells later line the neural a hollow cylinder with an inner ectoderm and an tube and are called neurectoderm, germinal layer, outer entoderm. The embryo proper then develops or ependymal layer. Their derivatives are the pre as a focal thickening of the ectoderm called a cursors of neurons and glia, and these accumulate primitive streak. Between the entoderm and the at first just outside the lining to form a "mantle." thin blÃ¡stula vesicle wall is a space, the yolk sac, By varying processes of proliferation, migration, sometimes containing maternal erythrocytes. It and grouping, these germinal and differentiating is assumed that the layered embryo that follows cells form the future nuclei, cell layers, and zones results from gastrulation analogous to that in the of the gray matter. The neurites of the nerve cells simpler vertebrates. Man develops through these form the interconnections, the future fiber systems stages somewhat similarly (115), the inner cell and neuropil within the central nervous system, mass becoming an embryonic disc with an epi- and the nerves that communicate between the

central nervous system and peripheral tissues. The laying down of two general regions of the neuraxis vascular system develops according to precise pat or whether it is responsible for a very complex terns related more to the apparent local needs of mosaic of the future nervous system will be con each region than any over-all gradient pattern (20, sidered later. 35). It is the sum of these processes that delineates Speculations concerning the transformation of the developmental anatomy of the vertebrate the ectoderm into neurectoderm have ranged from nervous system. Some details of them will be given considerations of cell radiations to specific chemi later. cal inductors. Experimenters have tried almost Two other sources of cells contribute to the everything under the sun from organic substances peripheral nervous system and related structures. to extracts of embryonic or adult tissues. It is true The neural crest (62) appears as a transformation that most of these will induce prospective neural of the ectoderm along the lateral margin of the plate to become some kind of neural structures, neural plate at its junction with the prospective but it is becoming increasingly evident that this is different from producing a complete "individuat epidermis and lies as a strip of cells between the ed" nervous system (13, 104). Holtfreter (56, 58) central nervous system and the epidermis when the neural tube has formed. From it are derived spinal and autonomie ganglion neurons, pigment cells (melanocytes), nerve sheath cells, leptomeninges, much of the connective tissue of the head and some of the trunk, and certain peripheral neural organs such as the adrenal medulla and chromaffin system. In some lower vertebrates it forms cartilage. Still other focal transformations, called placodes, occur as thickenings in the lateral ectoderm regionally associated with the cranial part of the neuraxis. They are very much like focal "neural crests," and contribute to parts of sense CHART1.â€”Somesteps in the development of a vertebrate brain (man). (1) Earliest neural plate (hatched) with under organs (olfactory epithelium, ear, and lens) and, lying mesoderm ; (2) early neural plate and folds (hatched) in with neural crest cells, to ganglia and possibly stage of early somites; (3) configuration of whole neuraxis about 30 somites; (4) early cerebral vesicle stage of brain and connective tissue. brain stem with migration areas of Bergquist and KÃ¤llen approximately indicated ; (5) fetal brain ; (6) outline of mature INDUCTIONOFTHE NEKVOUSSYSTEM brain. Based on Witschi and original sources. Schematic, It is generally agreed that in normal amphibian lateral views. development the mesoderm forming the roof of the archenteron (primitive gut) of the gastrula is re concluded that a common denominator in all these sponsible for the transformation of the overlying experiments with artificial inductors was damage ectoderm into the neural plate. (Reviews: Holt- to cell surfaces and that breakdown products of freter and Hamburger [59],Spemann [90], and ref this cellular disintegration acted as artificial in erences below). A similar mechanism is probably ductors. at work in other vertebrates, including birds and Induction is a trigger reaction in which cells mammals (38, 39, 41, 53, 67, 84, 85,115). Precisely having differentiated as far as ectoderm are how the mesoderm (the "organizer") does this is steered into one of the remaining paths of further not known, but the problem has stimulated a tre differentiation still possible for them. Experimen mendous number and variety of experiments, in tally, it can be shown that just before neuraliza- cluding extirpations, biochemical and immuno- tion the ectoderm has the "competence" to be logical studies, transplantations and culturing of come epidermis, neurectoderm, or mesodermal tis various parts of the embryo. Some of these illus sue, although its normal "prospective" path is to trate the problem. It may be said summarily at the ward neurectoderm. It may be considered to have outset that the anterior or prechordal part of the a limited number of chromosome-controlled meta mesoderm, the roof of the archenteron or primitive bolic pathways open to it, and induction is the gut in amphibia, "induces" anterior parts of the process by which the mesoderm activates or in brain, while caudal parts of the mesoderm (future hibits these potencies (Waddington [104]). Once notochord) induce brain stem and spinal cord. The the cell has differentiated to neurectoderm, it is mesoderm is also apparently responsible for the irrevocably limited to the pathways of differentia differentiation of the neural crest and placodes. tion open to neurectoderm. Whether this early induction simply involves the Molecular and biochemical aspects.â€”Weiss (110)

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1957 American Association for Cancer Research. 254 Cancer Research has put forward a hypothesis involving cellular chemical measurements of embryos as a whole and molecular ecology that is helpful in thinking about of their parts, however, is available. (Reviews: [11, transformations in cells. It applies not only to early 13, 80, 97,103]). In amphibia, the mesodermal and neural induction but to thinking about how almost ectodermal cells involved in the inductive process any cell influences the future differentiation or rapidly acquire considerable histochemically meas transformation of another cell. He says: "Let us urable cytoplasmic glycogen, and intense glycoly- suppose that the surface of the 'inducing' sub sis that can proceed anaerobically is demonstrable stratum is saturated with a certain species A of in the mesodermal region. The presumptive nerv polarized molecules of such configuration as to ous system requires considerable oxygen, in con match precisely one single component of the mo trast. Between the presumptive neural plate and lecular populations a, b, c, d, etc., of the overlying the mesoderm there is intensification of sulfhydryl ectoderm cells. Due to their complementary ribonucleoproteins, and these substances then in shapes, these two types, A and a, would form crease in both the neural plate and inducing strong unions. Thus, given a certain degree of mo mesoderm. bility of the cell content, all of the a units will These studies indicate some possible chemical gradually be trapped along the surface exposed to mechanics that drive and implement protein syn A, just as a film of antigen traps antibody mole thesis during inductive transformation, but much cules. Faced with a different substratum, contain remains to be learned about how the proteins are ing key molecules B complementary to b, the made. Indeed, there is some question whether early same ectoderm cell would become covered with a b embryos make up many of their proteins from layer, furnished again from its own stock, and simple building blocks at all. Schectman (87, 88) thus become turned into a wholly different course advances the concept, factually supported, that of differentiation. many of the embryo's proteins (measured as anti "Progressive determination would occur through gens) are originally maternal in origin. Macromole- a succession of such steps. A given contact situa cules of a wide variety are constantly obtained by tion would bring a certain key species to the sur the early embryo from the original maternal face. Its residence there would affect the chemical source, whether it is from yolk cells or through the processes in the interior, entailing presumably placenta. That the embryo is dependent on mater further regrouping along internal interfaces, set nal sources for normal development is suggested ting off a chain of effects which will reach the nu by the failure of early mammalian embryos to cleus and chromosomes, whose reactions, in turn, survive and grow in artificial surroundings unless will rebound on the chemical composition of the they include adult tissues and serum. Among cytoplasmic population. As a result, new com other functions, the maternal molecules might act pounds will arise, and when the cell is later faced as (environmental) templates in conjunction with with a new contact substratum this may attract the embryo's own genetic machinery to manufac some of these new species, initiating the next ture like or complementary substances, or partly phase of differentiation, and so forth. At any one dismembered molecules might also act as sub stage, the cell will thus have only a limited assort strates to stimulate enzyme formation. ment of specific key species, and its reaction to There are many changing patterns of antigen 'inductive' surface contact will therefore vary with make-up during early embryogenesis that are tem time. This is the molecular version of what is porally linked to morphologic differentiations. A usually referred to as the development of respon well studied example, though it does not directly siveness, or 'competence,' in embryonic cells." concern neurogenesis, has been presented by Waddington (104), on the other hand, con Ebert (28-30), who showed by immunologie tech ceives of the passage of evocating or inducing sub nics that myosin appears in the chick just after in stances into the cells and their more direct action vagination of the mesoderm into the primitive on the surfaces of microsomes rather than on the streak. It becomes widespread in the presumptive outer cell surface as in Weiss' model. In support of mesoderm, then localized more and more into the this idea is the increase in number of microsomes anlagen of the heart as that organ shows signs of during induction in cells concerned, and the fact developing. The mechanism of the relative dis that microsomes are nucleoprotein in nature links appearance of the myosin has not been explained them to protein synthesis, a characteristic aspect yet, but a number of antigens may come and go in of differentiation (BrÃ¤chet[13]). early embryos, some related and some not seem Details about measured biochemical processes ingly related to adult ones. Early embryonic brain involved in neural induction are relatively scant, contains some antigens common to later stages but despite careful investigation. A large array of not to adult brain. As Schectman points out, it is

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1957 American Association for Cancer Research. HICKSâ€”DevelopmentalNeurology 255 presently hard to know which proteins are the to spinal cord, the relative proportions and rela products of differentiation and which ones are in tions of the major divisions of the brain, and the volved in the differentiation process. formation of the anlagen of components of the Morphology.â€”The actual morphologic aspects peripheral nervous system are determined here. of induction of the nervous system have been Severe deformities involving the primordia of the much studied. Dalcq (21) cut amphibian embryos neuraxis that lead to death of the embryo are rela "in half" at gastrula stages, rotated them 180Â°, tively common in teratology, and in at least a few and reapposed the halves, whereupon two nerv instances the earliest neural inductive processes ous systems formed. By this procedure he was for various reasons seem to be abnormal (38, 39). able to deduce what part, how much, and how long the mesoderm was able to influence the ectoderm How DOES THE NERVOUSSYSTEMEVOLVE? in each half. The strongest evocator of neural tis With the establishment of the neural plate, the sue was the presumptive prechordal material, and next problem is: how does a whole, complicated its strength fell off caudally and laterally from its nervous system arise from it? Virtually all the antero-medial position. Normally this gradient work on the induction of the nervous system as produced the forebrain anteriorly, the brainstem sumes that the central neuraxis is divided into a and cord caudally, and the neural crest and front, middle, and back part, the archencephalic placodes laterally. Experimentally, maximal in and deuterencephalic divisions tapering to the duction produced forebrain-like structures, the spinal cord. Like the germ layers, these parts de weakest effect resulted in melanocytes (neural scribe the embryo at a certain time and reveal crest derivative). Dalcq held that one inductor little about the adult. The popular division of the was responsible. neuraxis into several vesicles in the early neural Niewkoop (81) showed that the time and inten tube stages is similarly descriptive.1 To look deep sity of the inductive influence were normally a re er into this, a good deal of work has centered on sult of the gastrulation movements of invagination the study of the proliferation and migration cen at the blastopore. Prechordal mesodermal cells in- ters in the embryo neural tube that form a mosaic vaginated first, passing forward from behind under of the future brain and spinal cord, the mechanics the whole prospective neural area, exerting a maxi of these morphogenetic processes, and factors that mum neuralizing effect. However, he concluded influence the development and organization of that the chorda-mesoderm cells that followed in nerve cell fibers centrally and peripherally. Some hibited the process, forming a gradient of neurali- of these may be presented. zation strongest anteriorly and falling off laterally Mosaic of the future nervous system.â€”It has been and caudally. Eyal-Giladi (32) transplanted pro known for a century and a quarter that the nerv spective nervous system to other parts of the em ous system shows segments or "neuromeres," and bryo, and from what did and did not develop in studies of the mosaic of the proliferation centers the transplant interpreted what influence the un and migrating cells that generate the brain and derlying tissue had had on it. The duration of con spinal cord have engaged the attention of many tact during morphogenetic movements seemed to investigators, including Bartelmez (4), Holmgren be a prime factor, as in Niewkoop's work, but the (54, 55), Adelman (1), Coghill (17), Streeter (99), conclusion was that two inductors acted. Holt- Herrick (48, 49), Tilney (101), Bergquist (6), and freter (58) believed that capacities in the anterior Rudebeck (83). Wenger (113) has demonstrated inductive region to produce both neural and meso in the early chick spinal cord the mosaic of its dermal tissues were based on qualitatively differ future neural constituents, showing that cell ent substances. Toivonen (102) and Waddington groups have specific origins in the neural tube (104) proposed that the inductors are the result of analogous to those in the brain. Bergquist and distinct permeating substances and that one may KÃ¤llen (see several joint and single references to be a pure primary neural inductor and the other Bergquist or KÃ¤llen) have carried this approach may induce both spinal cord and associated meso much further on a comparative basis than have dermal structures. other investigators. They have sought a common Implications.â€” Why is this problem of the in basic pattern of proliferating areas in the verte duction of the nervous system important? It is the brate embryonic brain that would account for time when the basic plan of the whole future nerv ous system is first laid out, and the minutest devi 1The corresponding topographical division of the adult central nervous system into forebrain (telencephalon), in-be ations in the process can be magnified into the tween-brain (diencephalon), midbrain (mesencephalon), hind- grossest malformations. The bilateralness of the brain (medulla or metencephalon), and spinal cord is certainly brain and the eyes (2), the gradient from forebrain useful, although arbitrary.

both similarities and differences in the ultimate tographs are hard to convey (68, 69). The fore- adult structures of various species. They note that brain in the early cerebral vesicle stage is divided the many vertebrates show a sequence of prolifera into a roof or dorsal telencephalic migration area, tions in the germinal layer of the early neuraxis which gives rise to the future pallium or cerebral that suggests a series of inductions. The first wave mantle. From the floor or ventral telencephalic mi of activity produces a series of six slight bulges, or gration zone evolve certain future basal nuclear proneuromeres, faintly evident in the whole early or subpalliai structures. The latter shows three (in neural tube (about 10 somites in a mouse). These some species two) longitudinally disposed colum are short-lived but are followed by a second wave nar migration zones which are fused caudally in of more bulges, called neuromeres, which reach a the prospective preoptic region. Rostrally they are total of 21 at around 20 somites, and a third pat labeled a, 6, and c lateralward. With some slight tern of proliferation centers, the migration areas, exceptions they seem on a comparative basis to be follows on these. The migration areas are visible homologous among vertebrates and give rise to only in the brain and brain stem and form a com similar olfactory and striate nuclei. Column c de plex pattern which gives the appearance in a re velops two successive migrations (c1 and c11)to constructed embryo in the early cerebral vesicle form a number of subpalliai structures, and these stage of a network spread over the outer surface masses of migrating cells then divide themselves of the neuraxis. The net is represented by very further into internal and external components. In faint fissures, the net spaces by faint bulges. The mammals the first migration of cells, c1,moves out migration areas give rise to one or more packages from the neurectoderm to form an external and an of migrating cells that form specific nuclei, layers, internal part. The external part (c1external) forms and masses of neural cells that later compose the the nucleus of the lateral olfactory tract anteriorly adult brain. and the cortical amygdaloid nucleus behind. The The pattern of the migration areas (Chart 1) in internal portion (c1internal) becomes rostrodorsal- the lining of the neural tube is formulated as a ly the globus pallidus, and caudoventrally the series of transverse bands of cellular proliferation central amygdaloid nucleus and anterior amygda intersected by four longitudinal columns of pro loid mass. The second migration occurs and gives liferating cell centers. The longitudinal columns rise to an outer part, the putamen, and an inner correspond to the classic dorsal somatosensory, part, the rostral caudate nucleus. How a second dorsolateral viscerosensory, ventrolateral viscero- migration of cells can overtake an earlier group of motor, and ventral somatomotor columns. The cells and come to lie lateral to it can be visualized dorsal column extends only to the isthmus fold, the when it is realized that the forebrain is changing dorsolateral as far as the forebrain, the ventrolat shape during this growth process. For example, the eral to the diencephalon, and the ventral to the proliferating ventricular surface c was vertical midbrain. There are thirteen transverse bands when it gave rise to c1,but by the time it gave rise (also called postneuromeres). The intersections of to group c11it was lying horizontal and had also the first seven of these with the dorsolateral and been pushed forward. Thus, the derivatives of c11 ventrolateral columns, for example, compose the were in part brought forward and relatively lateral migrating centers for the future forebrain, dien to some of the c1regions which are displaced cau cephalon, and midbrain. These are given zonal dally. Different vertebrates, of course, differ con names usually arbitrarily related to future adult siderably in the degrees and proportions in which regions. The divisions of the medulla-to-be are the various migration centers develop. Comparing numbered in segments corresponding to a trans reptiles with mammals in respect to some deriva verse band and a longitudinal column. Chart 1 in tives of c, the nuclei of the lateral olfactory tract corporates a free sketch based on some of KallÃ©n's region are approximately homologous; the large- and Bergquist's reconstructions to give some idea celled part of the reptilian ventrolateral area cor of the network of migration areas. responds to the globus pallidus and ganglion of Homologization on an ontogenetic basis is diffi Meynert, while the nucleus centralis corresponds cult, especially when biologists disagree on what to the mammalian central and cortical nuclei. Part homology means (deBeer [23], Szarski [100], and of the ventrolateral area and intermediolateral Herrick [48]). Kallen and Bergquist attempt it by areas of the reptilian subpallium are derivatives of tracing the adult structure back to migration and c11,but as composite adult structures they are not proliferation centers and especially by tracing the regarded as homologs of the caudate nucleus and migration centers forward to whatever they are to putamen of the mammal. produce in a given vertebrate. Some examples may Such comparative studies reveal that there is be given, even though word pictures without pho an extensive mosaic of the future brain laid out

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1957 American Association for Cancer Research. HICKSâ€”Developmental Neurology 257 very early in embryonic life and that many of the which it is transplanted while restitution occurs in divergent patterns of development of vertebrate the defect. Normal development or a good fac brains have a common meeting ground in these simile of it results. The loss of a substantial part, beginnings. Here are some of the first visible mor- or large numbers of primitive cells, of the early phogenetic expressions of the genetic processes neuraxis in amphibia (26, 27, 47), birds (46), and that determine whether the brain will fit an alli mammals (50, 53) can in many circumstances be gator, a man, or whether it will function har restituted from remaining proliferative sources, moniously at all. provided certain inductive processes are not also Tilney (101) compared the morphogenesis of the interfered with. Thus, the early mosaic we have cerebral cortex of the opossum, rat, cat, and man, been speaking of is prospective and has a potential and noted its relations to simpler vertebrate fluidity as to what it can do in abnormal circum brains. The neocortex of these mammals with its stances. As development proceeds the fluidity is six laminations derives from three successive mi gradually lost in a generally head-to-tail sequence. grations from the germinal layer of certain regions If regeneration or capacity to "remodel" were of the cerebral vesicles. The parts of the vesicle that purely an experimental problem, the matter would form the base of the olfactory bulb (paleocortex) have little practical medical importance. The fact and the lower part of the mesial walls that arch that regeneration and restitution can in some cir over the thalamus (archicortex) continuous with cumstances occur to a remarkable degree after the olfactory bulb do not have these complex mi injury even in mammals means that destructive grations but mimic the ontogeny of simpler verte injury does not always result in malformation. brates, like reptiles. The future septum, mesially, The source of neural tube building blocks, the shows no layers. The neocortex is begun when the germinal layer, appears to be one or two to a few first migration of cells forms a lamina in the middle cells thick, and mitoses are relatively uncommon lateral vesicle wall. Certain tract beds, especially in the mantle and peripheral differentiating cell thalamo-cortical radiations, become prominent as populations. With colchicine Watterson has shown a result of the appearance of numerous spindle in the chick that this layer of potentially mitotic spongioblasts that outline where the fiber tracts cells is considerably thicker than usually supposed will be. The first migratory cortical lamina thick (Watterson [105]; see also Sauer [86]). When Det- ens meanwhile and becomes tri-layered corre weiler (27) extirpated half a neural fold of an am sponding to the zonal, external granule and exter phibian embryo, he attributed the restitution of nal pyramidal layers of the cortex. A second mi the fold to both germinal cells and cells not usually gration now brings a new fourth layer under these, considered to be germinal. Burr (15, 16) in similar the future internal granule layer. Then, during the experiments concluded contrariwise that regenera early pouch stage of the opossum, last fetal days tion came from the conventional neurectoderm. of the rat and cat, and in midgestation in man, the This seems to be the principal source of regenerat third migration moves out to form the internal ing cells as far as has been determined in mammals pyramidal and multiform layers, completing the (53). Notwithstanding, it seems reasonable that six. The corpus callosum tract bed cells (absent in primitive cells that would not usually divide again the opossum) first grow down mesially under the might do so in unusual circumstances. cortex from the frontal and parietal regions in From the beginning, the nervous system shows front and above the foramen Monroi. They then tendencies to regionally unequal growth, such as cross in the midline through the thin mesial archi the larger cephalic end, neuromery, various bends, cortex inducing the latter to form the induseum and variations in cell distributions. Many things griseum above, hippocampus behind, and subcal- besides simple proliferation enter into this. In a losal preseptal area in front. meticulous study of the patterns of mitotic activi Cell mechanics in morphogenesis.â€”The previous ty in the chick embryo spinal cord from 2J to 8^ sections dealt with some aspects of organization of days, Hamburger (42-44) and Levi-Moiitalcini cell aggregates. Do we know anything about the (76) and Hamburger and Levi-Montalcini (45) individual cells and how they behave normally and found that the determination of mitotic activity under abnormal and experimental circumstances? was governed by several interacting factors. How The cells of the early brain and spinal cord up to complicated and sometimes unexpected these can the closing of the tube are still rather flexible in be is illustrated by some of their findings. One their prospective capacities for development. might have expected greater mitotic activity in Transplanting one part of the early neuraxis into the spinal cord at the levels of the developing another region, if done early enough, results in in limbs but would not probably have expected the corporation of the "foreign" part in the region in basal (ventral) plate to differ greatly from the alar

(dorsal) plate. Actually, the alar plate showed orienting factor is the towing effect that a develop much higher levels of mitotic activity, and it ing limb or other organ exerts on a nerve fiber. reached a peak at 6 days, whereas the basal plate The distance between a neuroblast and the target peaked at 3 days with no special activity at the of its fiber is not so great in the beginning as its limb levels. It turned out that uniform ventral later relations in the adult suggest, so that after gray columns were produced throughout the cord the fiber gets to the limb, subsequent limb growth at first, and this occurred earlier than did the dor carries it along "passively." sal. Two things happened later to account for the Gradients, distance chemical influences, neuro- ultimate reduction in the size of the motor columns biotaxis, and electrical fields are currently less in the cervical, thoracic, and sacral regions, leav popular as concepts to explain the guidance of ing those at the limb levels proportionately larger. nerve fibers than formerly, but the trouble an One was that many motor neuroblasts degenerated infant nerve fiber will take to make certain con in the cervical region where they were not needed. nections is impressive. Mauthner's cell, a single The other was that "excess" cells in the thoracic huge neuron in each side of the medulla of the tad and sacral regions moved to the ventromedial part pole, sends a long conspicuous fiber to the animal's of the cord to become the preganglionic autonomie tail. The cell can be spatially disoriented and cell columns. The alar plate growth behavior was blocks placed in the path of its fiber, but the fiber less easily explained. Its lag behind the motor col turns and dodges until it finds its way to the tail umns may in part have been due to the slower de (review, Stefanelli [96]). The facility with which velopment of the posterior horns and related inter certain developing nerve fibers, after section and calated neurons. The larger size of the posterior disorientation, can find their way back to the cen root ganglia supplying limbs was related to the tral nervous system and make the right functional greater number of mitoses in the ganglia of the connections can be partly explained by assuming brachial and lumbosacral levels than elsewhere. specific chemical surface reactions (Weiss [110, Further difference in size resulted from degenera 112]), but much remains to be learned. The extra tion of partly differentiated neuroblasts in the cellular spaces and matrix are as much the animal thoracic and cervical ganglia but not in the limb as the cell units, a matter emphasized by Weiss ganglia. particularly, Holtfreter (57), and Schmitt (89). Influences on development of nerve cells and fibers. Opie (82) has shown what an extraordinarily â€”¿Allsorts of hypotheses have been advanced to watery milieu the molecular and cellular compo explain how the intricate fiber connections of the nents of the embryo operate in. The more we un nervous system are fabricated and how the first derstand the matrix perhaps the more we shall neuntes of the neuroblast get started. Much cur know how it makes cells do the things they do. rent thinking attributes the guidance of the fiber The metabolic changes of the cerebral nerve to surface reactions between the fiber and the cell itself accompanying maturation and the matrix in which it finds itself (110, 112). The first growth of its fibers prior to myelination and matu pseudopodial projection of the primitive neuro rity have been little studied except by Flexner and blast cytoplasm is apparently exploratory, and in his associates (reviews [36, 37]). In rats, swine, and experimental circumstances a fiber aligns itself guinea pigs growth of the nucleus is a predominant along oriented surfaces such as fibrin strands, col feature in the neuroblast, but as the cell becomes umns of cells, or along other nerve fibers already a recognizable neuron a shift to increased aerobic laid down. Rapidly proliferating centers seem to metabolic processes occurs. Cytoplasmic matura attract young neuntes nonspecifically. Fibers from tion is accompanied by formation of protoplasmic neuroblasts of the cervical spinal cord may be at fibers, Nissl material, a nucleolus, and synthesis of tracted to the appropriate developing limb bud, certain enzymes. Following these the beginning of but they will also grow toward a transplanted de functional maturation is shown by measurable veloping eye or nasal placode. Weiss speculates that electrical activity and, in appropriate cases, evi two proliferation centers, due to local dehydra dence of motor activity. tion, will tend to orient the extracellular matrix Peripheral factors influence the development into lines running between them. Nerve fibers of central neuroblasts and their fibers in several sprouting out from the spinal cord center would be ways, but the relations are not simple, and some oriented to grow toward the regional proliferating of the functional aspects will be discussed later. limb bud center. Sharp deflections of fibers in the As early as 1920 Detweiler transplanted a limb to brain may result (early) if they contact oriented the trunk in a developing amphibian, and this lines in the matrix, or (late) they may simply fol caused overgrowth of the corresponding innervat low already established fiber bundles. Another ing spinal ganglia. It had been known earlier that

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1957 American Association for Cancer Research. HICKSâ€”DevelopmentalNeurology 259 an absent limb caused undergrowth of the corre related type of specificity in muscle innervation. Stone and Sperry extended Matthey's experiments sponding ganglia. In amphibia where the optic tracts cross completely, removal of an eye before and explored other neural systems. the fibers contact the optic tectum results in un- Specificity in neural organization.â€”In Weiss' derdevelopment and atrophy of the neurons with amphibian experiments a single muscle or a whole which the optic fibers would have synapsed. The limb was transplanted to a position adjacent to a process is complex, and it not only affects these normal limb early in development. The limb de neurons but also subdues the mitotic activity in veloped essentially normally and was innervated the neurectoderm of the tectal region and migra by branches from those to the normal limb. The tion of neuroblasts from it (73). In mammals the coordinated movements of its muscles functioned effects of the optic nerves on development of sec in a synchronous pattern identical to that of the ondary centers is still poorly understood for obvi normal limb. Each muscle conferred upon the ous technical reasons. Still other patterns of this nerve growing into it a mark or a sign, apparently sort can be demonstrated. Extirpation of the oto- at the molecular level, that conveyed to the neural cyst including the eighth ganglion primordium in center precise information as to just which muscle the 2-day-old chick embryo is followed by normal it was connected with. If the transplanted limb differentiation of neurons of the secondary ves was put on backward, the nerves that grew into tibular nuclei up to a point. Then after they are the muscles were informed exactly what the mature degeneration occurs, and this is greatest in "name" of the muscle was that each innervated. the nucleus angularis, less in the nucleus magno- This information was so precise that the move cellularis, and least in other vestibular centers. ments of the transplanted limb synchronously Angularis seems to depend solely on affÃ©rentsfrom mirrored every movement of the adjacent normal the ear, whereas the other nuclei are "protected" limb. This movement persisted automatically de by having additional synapses from other sources spite its inconvenience to the animal. (Levi-Montalcini [75]). Clearly, there was more to this than a muscle Still another interesting influence on central contracting in response to a nerve that had be nervous system growth is the stimulating effect come specified to it. In normal development a that some as yet unknown substance in a mam much more complex system of coordination proc malian sarcoma has on the development of ganglion esses was involved. At the same time that the spe cific muscle was applying its own "name" or neurons in the bird (14,44,77). Planted near the leg bud of a 2-day chick embryo, mouse Sarcoma 180 "sign" to the motor nerve that had grown into it, stimulated the regional spinal and sympathetic proprioceptive afferent fibers were also being ganglia to become abnormally large owing to in marked. The central connections of these afferent creased numbers of primitive neuroblasts and nerves were also becoming specifically integrated rapid differentiation. Fibers from these ganglia into the corresponding central motor mechanism grew out and invaded the tumor, but there was no that was developing. One of the harmonious re trophic effect in the somatomotor nerves. Planted sults of this process in respect to limbs was the in the extra-embryonic membranes, the tumor evolution of a coordinated mechanism for walking stimulated the same kind of hypertrophy of cells. and running, and this machinery developed in a Nerve fibers grew out prematurely and in exces self-determining manner characteristic for the ani sive numbers into the viscera, often passing mal. Weiss exchanged the right and left front limbs through blood vessel walls to form fibrous prolif in embryos and also in older larval amphibians so erations in their lumens. Considering how nicely that the two limbs faced backward in a reversed balanced peripheral innervation usually is, the tu symmetry. Innervation appropriate to the specific mor substance must be considered to be an ex left and right sets of muscles developed so that traordinary alterant of development. when the animal should have walked forward its front limbs walked backward. When the animal SPECIFICITY IN NEUHAL DEVELOPMENT was stimulated to escape by being held by the Weiss (106) and Matthey (78) first fixed special tail, its front limbs frantically ran toward the attention on the extraordinary specificity of the painful stimulus. This occurred in both swimming components of the nervous system. Matthey cut and terrestrial species. The animals never correct the optic nerve of the newt and discovered that the ed these patterns. fibers regenerated and found their way back to the Stone (98) and Sperry (92-94) explored speci right part of the brain so precisely that normal ficity in the visual system of amphibia. Stone ex vision was recovered. Weiss at this time and in perimented with the eyes of Amblystoma at many subsequent extensive studies (107-109) showed a stages of development and with adult Triturus in

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1957 American Association for Cancer Research. 260 Cancer Research which a capacity for an embryonic type of regen was cut and the distal end experimentally made eration persists much longer than in most animals. to regenerate into the central stump of the contra- Eyes surgically removed and replaced promptly lateral root. Regenerating fibers found their way degenerated except for a ring of peripheral cells of to proper central connections even though the his the ciliary margin. From these cells a complete tologie picture of the abnormal root entrance was functioning new eye developed in about 2 months, one of chaos. provided the eye was normally oriented when it Variation in different vertebrates.â€”Development was replaced. If both eyes were removed and one of specificity of the cells of the nervous system was rotated 180Â°andreplaced in its own orbit, re varies in different members of the vertebrate king generation occurred, and fibers of that eye con dom and in different parts of the nervous system nected up with the optic tectal cells precisely as in a given animal. In muscles the capacity to re they had previously. (The other eye was discard model the specificity persisted for a long time, but ed.) However, images that used to be received on in the eye it was "crystallized" quite early in de the lower part of the retina were now received on velopment. That the fine structure of the nervous the upper part and vice versa, and the animal saw system, at least below the pallium, is apparently everything upside down. It responded accordingly irreversibly set by the time of maturity in mam and lept upward at a lure held below eye level, and mals as well as lower forms is supported by ob dived down in its tank toward a lure held above it. servations in rats and man. Sperry (1945) trans If the right eye was transplanted to the left side, posed sensory nerves in the hind legs of adult rats. but not rotated, objects in front were seen behind By this stage of development the nerves were spe and vice versa. This polarization of the retina first cific for coordinating sensory stimuli with motor showed specificity at about the time the first responses of the right and left sides. The nerves motor responses occurred in the embryo and was regenerated anatomically, but a stimulus to one well established by the time the heart was beating leg induced an inappropriate motor response in the prominently. Rotation of the eye after this time other. The same sort of thing is familiar in man. resulted in the characteristic dysfunctions just When a hypoglossal or spinal accessory nerve is described. Sperry made similar experiments in fish, anastomosed to the distal part of a cut facial nerve, frogs, and newts and found the same specificity. the hypoglossal nerve is never functionally trans He also studied histologie sections and found that formed into "facial" nerve, and it never takes over the nerve fibers were disarranged at the site of real facial nerve function (Coleman [19]). regeneration but had ultimately found their way Implications.â€”These experiments illustrate back to the proper centers. Altogether, these ex that much of the basic structural patterning of the periments indicate that "optic fibers arising from nervous system is built in by the developmental different points in the retinal field differ from one processes in a predetermined way and the degree another in quality," just as Weiss showed for the of specificity is extremely refined. This does not motor nerves in muscle. deny that a nervous system is what it is, an adap Sperry (94) and Miner (79) investigated other tive or adjusting mechanism. Depending on the central-peripheral connections. If a segment of number and complexity of the repertory of alter belly skin in a tadpole was exchanged with one nate neural mechanisms available to it, an animal from the back, the frog that grew up had a patch can compensate for malfunctioning parts. The sal of white belly skin on its back and back skin on amander with its legs on backward had neither a its belly. When the displaced belly skin was stim repertory of alternate limb mechanisms nor a ulated the frog wiped its belly. The displaced belly cerebral cortex to implement them if it did. Sperry's skin had conferred its positional identification on rats could not "learn" to compensate for the the nerves that grew into it and histologically crossed nerves in the hind limbs, but in experi these were the normal regional nerves. In other ments in which the forelimb nerves were crossed experiments the developing afferent nerves of the some compensation through available alternative limb skin were removed, and adjacent trunk movements was accomplished. In more complex nerves were allowed to grow into it. The trunk mammals and man there is a considerable capacity nerves acquired the "sign" of the limb, and when for higher centers to dissociate motor coordination the tadpole became a frog these nerves mediated mechanisms and substitute other mechanisms limb reflexes, not trunk reflexes. Sperry also re when temporary or permanent injury interferes ported experiments involving the vestibular sys with normal function. Sometimes this leads to a tem in which the results were analogous to those in remarkable degree of compensatory function. the optic experiments. In still other amphibian There is presently no evidence that the actual experiments a posterior sensory spinal nerve root nerve fibers involved (as in the hypoglossal-facial

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1957 American Association for Cancer Research. HICKSâ€”Developmental Neurology 261 anastomosis) are ever "developmentally" altered in a given gene or part of a chromosome may be re the adult. sponsible for the development of a number of Most of what has been dealt with has concerned characteristics diversely represented in separate the early organization of the structures upon organs, cells, enzymes, and other attributes. De which future function will be based rather than the velopmental characteristics, as far as they can be chemical or physiological nature of the specificity. defined, come in a diverse assortment of pack Most neurochemical and functional studies relat ages, and it is often hard to define what is meant ing to behavior are carried out much later in de by one in the adult brain until a mutation reveals velopment than the "putting together" stage, but it. The seeming diversity of normal and abnormal the evolution of mammalian fetal reflexes has been forms (phenotypes) that is seen may depend more the subject of investigation (3, 60, 114). The neu on shades of environmental influence than on in- rochemical changes that underlie the extraordi numberable genotypes. Despite the enormous the narily refined degrees of specificity of functional oretical numbers of possible DNA codes, there development are still beyond biochemical methods may be only a relative few basic combinations that presently available. can accomplish successful development (Gold- schmidt [40]), and the number of possible or likely GENETICASPECTSOFNEURALDEVELOPMENT chemical configurations may be considerably less Genetics has been described as "the study of the than is inferred from the models. Answers to these origin, development, and distribution of individu questions may help to explain why the neuro al differences" (David and Snyder [22], in reference pathologist does not see an unlimited variety of to the nervous system), and it equally concerns malformations and why certain patterns seem to the mechanisms by which individual similarities crop up throughout the vertebrate kingdom. and species are perpetuated. These mechanisms Examples of mutations that are expressed as have their beginnings in the genetic material, the biochemical faults are well known, the chromo chromosomes. Recent biochemical studies of somal abnormality resulting somehow in a missing chromosomes and nucleic acids have culminated enzyme or groups of enzymes. Phenylketonuria, in the formulation of chemical models that aid in galactosemia, and Wilson's hepatolenticular de thinking about how this genie material may initi generation are examples, but it is not possible at ate and determine normal and abnormal develop present to know whether these solely represent bio ment preview of various concepts, DeBusk [24]; chemical defects at the end of the developmental popular summary, Horowitz [61]). line or something more complicated. In the idiocy The chromosome may be regarded as having a of phenylketonuria it is not known whether the protein core wound with a parallel pair of helical accumulation of phenylalanine impairs what chains of segmented deoxyribonucleic acids would otherwise be normal brain function or (DNA). The arrangement of the sequence of the whether the mutation also impaired the molecular usual four pyrimidine and purine bases in the structure of the nerve cells in other ways besides chain provides a theoretically almost limitless enzymes concerned with phenylalanine. In other variety of combinations, since the helixes have words, it is usually impossible to know at just millions of turns. Segments of DNA, perhaps cor what stage a developmental process first got off responding to the gene unit as it is popularly con the track and consequently what is a "primary" ceived in development, may act as templates, pos defective process and what is "secondary." sibly by imprinting a specific code on nuclear pro Most congenital anomalies are the result of tein or by forming RNA templates to be used in mutations or interference with developmental cytoplasmic protein synthesis. The remarkable pathways governed by the normal counterparts of degree of specificity that is implicit in the develop the mutated genes. Because the latter process re mental processes is made palpable by these con sults in a copy of a mutation the resulting abnor cepts. By the same token mutations that lead to mal animal is called a phenocopy (Goldschmidt biologic variation or frank abnormality are viewed [40]). The possibility that most phenocopies may as alterations in the coded templates. A mutated be the combined result of mutants that are not template results in a mutated protein in the initial ordinarily expressed and unusual environmental steps of development. factors has been suggested by Landauer (74). A How the genetic material ultimately translates third group of abnormalities results when the its code into the form and function of an adult or embryo or fetus is injured so as to destroy a part ganism is a matter of enormous complexity. There of its tissues. The best example of this is the ab is not a group of genes for the brain, another for an normalities that follow the various kinds of extir eye, and still another for a leg or a nerve. Rather, pative procedures employed by experimental em-

bryologists. Although the response to injury of any NEOPLASIA organism is primarily determined by its genetic The most fruitful applications of embryology to makeup, these responses tend to reflect patterns of oncology will probably come from an understand growth common to vertebrates, and they can even ing of how chromosomes govern cell differentia be designed not to imitate mutants. Ionizing radi tion, whether this follows a normal course, a neo- ation, anoxia, certain traumatic injuries and in plastic course, or some other deviation called ab fections may cause abnormal development of this normal development. The general problem is be sort in vertebrates in special circumstances but in yond the scope of this review, and only some par man such causes are rarely substantiated (51-53). ticular points as they fit into the problem of neural Ploidy and chromosomal changes during develop development have been considered. In clinical and ment.â€”It is at first disconcerting to learn that de pathologic practice the distinction has to be made viations from the usually accepted number of between neoplasms and malformations for the chromosomes in mammalia and other animal cells purpose of treatment, but the distinction is some is commonplace. Deviations in set multiples are times really impossible. Some growths involving familiar to biologists who work with plants, inver the nervous system as in von Recklinghausen's tebrates, and lower vertebrates. Animals that are neurofibromatosis, cerebellar "astrocytomas," vas apparently normal may have in their bodies so cular malformations, and tuberous sclerosis pre matic cells with half, double, or triple the usual sent features of maldevelopment at one time and complement of chromosomes. When this involves all the body's cells, tissue structure and function neoplasia at another, or both aspects may present themselves. The development of a retinoblastoma, may be affected. a neuroembryoma of the eye, which usually satis Fankhauser and his associates have investigated fies the criteria of a malignant tumor, is governed the role of ploidy in development of the nervous by a dominant gene with high expressivity. In its system in salamanders (33, 34). Interference with morphogenesis it possibly passes through a stage the second maturation division of the fertilized of malformation into neoplasia. On the other hand, eggs leads to the development of animals with a Zimmerman (116) has demonstrated in animals triploid number, or three sets, of chromosomes in (having an appropriate genetic makeup) that neo- all their cells. The size of individual cells in such plastic transformation can be induced in one or animals is larger than that in the normal diploid more of adult glial types directly without resorting animals, but the total size of the animals, and their to embryonal cells or to what is virtually unsub brains, is the same in both. (Tetraploid and penta- stantiated in any other form of development, ploid animals, which also sometimes occur, have "dedifferentiation" (Ephrussi [31]). The point is even larger cells roughly proportional to the that neoplasia in the nervous system is no more ploidy.) The triploid animals actually have a an entity or even a single form of abnormal differ smaller total number of neurons than do their entiation than it is in any other tissue (Huxley diploid brothers in the same brain volume. This is [64]). shown by histologie study. In certain "learning" One other aspect of neural tumors (and tumors tests to which they were subjected, the triploid ani in general) may be touched on. The inference is mals were significantly less gifted than their often drawn that, because two adult tissues origi diploid brothers. The results of the experiments nated from the same embryonic germ layer, they pointed to the fewer neurons in the brain as being will have similar characteristics. Some efforts have the factor responsible for their poorer per been made to dispel this myth (DeBeer [23]), and formances. the recent work of Horstadius (62), Spratt (95), The frequency with which deviations from the and Witschi (115) among others strengthen them. normal diploid state in man or other mammals Considerable discussion, for example, has always may, by unequal division or as a result of par surrounded the classification of the nerve sheath thenogenesis, have anything to do with the devel cells, the pia and arachnoid cells of the lepto- opment of the nervous system is presently specu meninges, and the tumors that imitate them. It lative. The variation in the total number of is often argued whether the leptomeninges and chromosomes that may be found in mammalian Schwann sheaths are neural tissues or connective somatic cells is normally very considerable (Beatty tissues, and, because they derive from the neural [5]). This is compatible with a concept that a pre crest, it is said that they must be neural. Recent cise chromosome number is most essential to cells work shows that this no longer has any meaning. in early embryonic development and that it may Pia-arachnoid is pia-arachnoid, and Schwann cells be less essential to the proper behavior of cells of are Schwann cellsâ€”and they may, if desired, be more differentiated tissues (King and Briggs [71]). designated as neural tissues because of their adult

functions and associations but not at all because 6. BERGQUIST,H. Zur Morphologie des Zwischenhirns bei of their embryonic origin. The neural crest gives niederen Wirbeltieren. Acta Zool., 13:57-303, 1932. 7. . Ontogenesis of Diencephalic Nuclei in Verte rise to leptomeninges, connective tissue of the brates. Lunds Universitets Arsskrift N.F. Avd. 2. Bd 50. head and trunk, Schwann cells, melanocytes, Nr 6, 1-54, 1954. adrenal medulla, and certain neuronsâ€”as dis 8. . On Early Cell Migration Processes in the Embry parate a group of tissues as could be gathered onic Brain. J. Embryol. Exper. Morphol., 4:152-60,1956. together. 9. BERGQUIST,H.,and KÃ„LLEN,B.Studies on the Topogra phy of the Migration Areas in the Vertebrate Brain. Acta If a further example is needed to show that so- Anat., 17:353-69, 1953. called embryonic layers are part of the embryo, 10. . Notes on the Early Histogenesis and Morpho not the adult, one may recall the adenoacanthoma genesis of the Central Nervous System in Vertebrates. of the uterus. The keratinizing prickle cell parts J. Comp. Neurol., 100:627-59, 1954. 11. BOELL,E. J. Energy Exchange and Enzyme Development of such a tumor are morphologically indistinguish during Embryogenesis. In: B. H. WILLIER,P. WEISSand able from epidermoid cancers elsewhere; that its V. HAMBURGER(eds.),Analysis of Development, pp. 520- origin can be traced back to the embryonic meso- 55. Philadelphia & London: W. B. Saunders Co., 1955. derm throws little light on its morphologic nature. 12. BOTD,J. D. Some Aspects of the Early Development of the Nervous System. In: H. WAELSCH(ed.),Biochemistry CONCLUDINGREMARKS of the Developing Nervous System, pp. 3-27. New York : Academic Press, Inc., 1955. Our knowledge of the early normal and abnor 13. BRÃ„CHET,J.Chemical Embryology. New York: Inter- mal development of the vertebrate nervous system science Publishers, 1950. is still fragmentary, and the fragments have natu 14. BOEKEB,E. D. Implantation of Tumors in the Hind Limb rally varied more in proportion to the interest they Field of the Embryonic Chick and the Developmental Response of the Lumbo-sacral Nervous System. Anat. have held for investigators than in their relation to Ree., 102:369-96, 1948. the whole of neurology. Most of the ground work 15. BURR, H. S. Regeneration in the Brain of Amblystoma has been laid in experimental neuroembryology of (Embryos). J. Comp. Neurol., 26:203-11, 1916. simpler vertebrates, but there is no longer doubt 16. . Determinants of Organization in the Cerebral Hemispheres. In: Localization of Function in the Cere that basic principles of development apply to the bral Cortex, pp. 39-48. Baltimore: Williams & Wilkins vertebrates as a whole and that differences are Co., 1934. chiefly a matter of complexity. 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Samuel P. Hicks

Cancer Res 1957;17:251-265.

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