Early Development of the Cranial Sensory Nervous System: from a Common Field to Individual Placodes

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Developmental Biology 276 (2004) 1–15 www.elsevier.com/locate/ydbio Review Early development of the cranial sensory nervous system: from a common field to individual placodes

Andrea Streit

Department of Craniofacial Development, King’s College London, Guy’s Campus, London SE1 9RT, UK

Received for publication 23 April 2004, revised 20 August 2004, accepted 23 August 2004 Available online 30 September 2004

Abstract

Sensory placodes are unique columnar epithelia with neurogenic potential that develop in the vertebrate head ectoderm next to the neural tube. They contribute to the paired sensory organs and the cranial sensory ganglia generating a wide variety of cell types ranging from lens fibres to sensory receptor cells and neurons. Although progress has been made in recent years to identify the molecular players that mediate placode specification, induction and patterning, the processes that initiate placode development are not well understood. One hypothesis suggests that all placode precursors arise from a common territory, the pre-placodal region, which is then subdivided to generate placodes of specific character. This model implies that their induction begins through molecular and cellular mechanisms common to all placodes. Embryological and molecular evidence suggests that placode induction is a multi-step process and that the molecular networks establishing the pre-placodal domain as well as the acquisition of placodal identity are surprisingly similar to those used in Drosophila to specify sensory structures. D 2004 Elsevier Inc. All rights reserved.

Keywords: Placode; Development; Nervous system

Introduction olfaction and vision. While some placodes are simple neurogenic centres, others such as the otic and olfactory The vertebrate head ectoderm contains unique neuro- placodes generate a multitude of cell types and undergo genic regions: the cranial sensory placodes. Like the neural complex patterning events once a columnar epithelium has plate, which gives rise to the central nervous system (CNS), been established. placodes are transient columnar, pseudostratified epithelia. Despite their long history in experimental embryology They arise at distinct rostrocaudal positions next to the (the term dplacodesT was coined in 1891 [von Kupffer, neural tube shortly after the start of neurulation and, because 1891]), the importance of placodes for sensory functions of their ability to generate neurons outside the central and their evolutionary significance as key structures nervous system, are excellent model systems to study both believed to have evolved along with the appearance of inductive interactions and neurogenesis. Placodal cells give higher chordates, placode development has been neglected rise to the majority of neurons that form the cranial sensory by modern developmental biologists until very recently. nervous system contributing to the cranial ganglia and the The availability of molecular markers specific for individ- special sense organs associated with hearing, balance, ual placodes as well as for particular cell types derived from them has now stimulated much new research in the field and has lead to exciting findings in placode induction, patterning and cell fate specification. An * Department of Craniofacial Development, King’s College London, Guy’s Hospital, Guy’s Tower Floor 27, St. Thomas Street, London SE1 excellent review has recently summarised in detail the 9RT, UK. Fax: +44 20 7188 1674. classical and current literature on tissue interactions and E-mail address: [email protected]. signals involved in the induction of individual placodes

(Baker and Bronner-Fraser, 2001). Here, I will concentrate on some of the earliest steps that initiate placode formation, asking the question of when and how placode induction begins and discussing the evidence for and against the view that all placodes arise from a common placodal field—the pre-placodal region —through a common molecular mechanism.

Cranial placodes: origin of diverse structures and cell types

Cranial placodes are regions of columnar epithelium that form between the 10- and 30-somite stage at precise positions along the developing brain (Alvarez and Navascues, 1990; Anniko and Wikstrom, 1984; Bancroft and Bellairs, 1977; Brunjes and Frazier, 1986; Croucher and Tickle, 1989; D’Amico-Martel and Noden, 1983; Hilfer et al., 1989; Mayordomo et al., 1998; Meier, 1978a,b; Mendoza et al., 1982; Romanoff, 1960; Schook, 1980; Van Campenhout, 1956; Wakely, 1976; Fig. 1B). The olfactory placode forms in the anteriormost position next to the forebrain; it gives rise to the olfactory and vomeronasal epithelium including their sensory neurons (Brunjes and Frazier, 1986), to a population of migratory GnRH neurons (Dellovade et al., 1998; Schwanzel- Fukuda and Pfaff, 1989; Wray et al., 1989) as well as to the glia that will ensheath the olfactory nerve (Chuah and Au, 1991; Couly and Le Douarin, 1985; Norgren et Fig. 1. Position of the cranial placodes in a 1.5- and 3.5-day chick al., 1992). The lens placode forms next to the optic embryo. (A) At the 10- to 13-somite stage precursors for different vesicle and is the only cranial placode that does not give placodes are segregated and occupy unique positions in the head rise to neurons; it is included in this review by virtue of ectoderm. Fate maps combined from Bhattacharyya et al. (2004) and D’Amico-Martel and Noden (1983). (B) At 3.5 days of development, all its close association with the eye and because like all placodes can be recognised morphologically and some have begun to other placodes, it arises from the ectoderm close to the undergo morphogenesis or differentiation. The olfactory placode lies next neural plate. The next more caudal placode is the to the future olfactory bulb, while the lens is surrounded by the retina. trigeminal, which occupies a large region next to the The trigeminal placode is situated adjacent to the midbrain, while the otic mid- and anterior hindbrain and forms the trigeminal placode next to the hindbrain has already invaginated to form the otic vesicle. The epibranchial placodes are positioned just dorsal of the ganglion (V) which has somatosensory function and acts branchial clefts. as a relay station for stimuli such as temperature, pain and touch from the skin, jaws and teeth. Molecularly, the trigeminal placode can be subdivided into two separate post-otic lateral line placodes, which develop into entities: the maxillomandibular and the ophthalmic por- mechano- and electroreceptors as well as the neurons that tions (Baker et al., 1999; Begbie et al., 2002). In fact, in innervate them (Northcutt et al., 1994, 1995; Schlosser, some amphibians two ganglia initially develop and fuse 2002; Schlosser and Northcutt, 2000). These primordia later (Northcutt and Brandle, 1995), while in some lower undergo remarkable migration to deposit lines of lateral vertebrates, two distinct ganglia form (Northcutt and line organs in the ectoderm of the head and along the Bemis, 1993; Piotrowski and Northcutt, 1996). Caudal entire body axis. Finally, the three epibranchial placo- to the trigeminal, next to the hindbrain, lies the otic des—geniculate, petrosal and nodose—are located more placode; it gives rise to the specialised epithelia of the laterally, just dorsal to the branchial clefts, and form the inner ear, including endolymph secreting cells, supporting distal parts of the VII, IX and X cranial ganglia that cells, sensory hair cells for the detection of sound, balance innervate taste buds, visceral organs and the heart and acceleration and neurons forming the cochlear– (D’Amico-Martel and Noden, 1983; Schlosser and North- vestibular ganglion (for review, see Brown et al., 2003; cutt, 2000). It is important to note that all cranial ganglia Fritzsch et al., 1998, 2002; Rubel and Fritzsch, 2002; have a dual origin: while their distal portions are placodal Torres and Giraldez, 1998). In fish and aquatic amphib- derivatives, their proximal parts are of neural crest cell ians, it is surrounded by a variable number of pre- and origin. A. Streit / Developmental Biology 276 (2004) 1–15 3

The bplacodal fieldQ hypothesis—support from pathway, to which additional components were then added experimental embryology to specify the distinct identities of individual placodes. The idea of a common placodal field provides a plausible Despite the structural and functional diversity of sensory mechanism by which this could happen: the ancestral organs and cranial ganglia in the adult, it has been suggested placode might have expanded and subsequently subdivided that the induction of all placodes begins through a common into separate placodes each then acquiring a specific cellular and molecular mechanism, which involves the function. formation of a common bplacodal fieldQ—the pre-placodal In favour of the placodal field hypothesis, histological region (Baker and Bronner-Fraser, 2001; Jacobson, 1963c; studies in mouse, fish and some amphibian embryos have Torres and Giraldez, 1998). For such a field to exist two pre- revealed a bprimitive placodal thickeningQ that surrounds the requisites have to be fulfilled: first, all placodal precursors anterior neural plate at late gastrula to early neurula stages should arise from a continuous domain of the embryonic (Knouff, 1935; Miyake et al., 1997; Platt, 1896; van ectoderm and second, this region should have unique Oostrom and Verwoerd, 1972; Verwoerd and van Oostrom, properties, being biased or specified towards a placodal 1979). This morphology is maintained in areas where fate, accompanied by the expression of a specific set of placodes form, while the ectoderm in the non-placode molecular markers. forming regions between them thins out. However, other The idea of a common pre-placodal region has been vertebrate embryos, like the chick, lack these morphological challenged recently based on developmental and evolu- characteristics. Based on previous findings by others and his tionary considerations (Begbie and Graham, 2001; Graham own experiments in amphibians, Jacobson (1963a,b,c, and Begbie, 2000). First, embryological findings suggested 1966) was the first to present a concise hypothesis for the that two types of placodes—the epibranchial and trigemi- complexity of cranial placode induction and the first to nal—can be induced through different tissue interactions suggest the existence of a common pre-placodal region. A and probably by different signalling molecules in a single large number of studies had determined that the induction of step and therefore do not share a common inductive different placodes involves similar tissue interactions: early mechanism (Baker et al., 1999; Begbie et al., 1999). signals from the endoderm and mesoderm promote the However, substantial evidence from both classical and formation of olfactory, lens and otic placodes (otic: modern experimental embryology indicates that placode Harrison, 1935; Orts-Llorca and Jimenez-Collado, 1971; induction is a drawn out process that involves a series of Stone, 1931; Waddington, 1937; Yntema, 1950; Zwilling, events before placodes become committed to their indivi- 1940a; see also Gallagher et al., 1996; nasal: Emerson, dual fates as exemplified for otic and lens induction (see 1945; Siggia, 1936; Yntema, 1955; Zwilling, 1940b; lens: below for detailed discussion). So far, there is no clear Jacobson, 1958; Liedke, 1942, 1951, 1955; see also Henry evidence that a specific placode can be induced in a single and Grainger, 1987, 1990). These signals, however, are not step from cells that during normal development never sufficient to trigger the development of a complete ear or contribute to the same or other placodes (see below). lens vesicle or a nasal sac. Later interactions with specific Furthermore, the fact that placode dinducingT signals or parts of the CNS seem to complete induction and to confer tissues differ from each other does not argue against a identity to individual placodes: while the forebrain promotes common pre-placodal state as they may represent final development of the nasal placode, the optic vesicle triggers that confer placode identity onto cells that are promotes lens development and the hindbrain otic placode already biased towards a generic placodal fate. formation (Haggis, 1956; Harrison, 1920, 1936; Jacobson, Second, while a long-standing view holds that placodes, 1963a; Reyer, 1958a,b; Street, 1937). Thus, it seems that an like neural crest cells, evolved with the emergence of initial step common to all placodes involve signals from the vertebrates (Northcutt and Gans, 1983), structures analo- mesendoderm, while later, more region-specific signals gous to the otic and olfactory placodes were recently confer placode-specific properties. identified in non-vertebrate chordates based on the expres- In a second series of critical experiments, Jacobson sion of molecular markers and the presence of ciliated showed that within the ectoderm adjacent to the anterior sensory cells (reviewed in Graham and Begbie, 2000; neural plate, (the PPR) cells are competent to give rise to Holland and Holland, 2001; Manni et al., 2001; Shimeld any placode (Jacobson, 1963c): when future placode and Holland, 2000). So far, there is no evidence that lower territory is rotated along its rostrocaudal axis at open chordates possess structures homologous to epibranchial neural plate stages such that the future otic region is now placodes, suggesting that these evolved separately from the in the position of the olfactory placode and vice versa, remaining placodes. It has been argued that their independ- placodes develop according to their new position (Fig. 2). ent emergence during evolution precludes a common However, when rotated later, placode identity seems molecular mechanism initiating the induction of all verte- already determined, but interplacodal tissue remains com- brate placodes (Graham and Begbie, 2000). However, it is petent to form new placodes. Thus, at neurula stages, cells just as likely that once an ancestral placode developed new within the PPR are able to generate a placode different placodes could arise by co-option of the same molecular from their normal fate. These early findings highlight two 4 A. Streit / Developmental Biology 276 (2004) 1–15

mesoderm and the young neural plate, either of which alone is insufficient to trigger the formation of a mature lens (Grainger, 1996; Grainger et al., 1988, 1997; Henry and Grainger, 1990; Zygar et al., 1998; for review, see Chow and Lang, 2001). In the absence of the optic vesicle, molecular markers for the presumptive lens ectoderm, like Pax6, are maintained, however, the vesicle is crucial for the ectoderm to acquire placodal morphology as well as for lens maturation as reflected by the expression of lens-specific crystallins and lens fibre formation (Furuta and Hogan, 1998; Kamachi et al., 1998; Li et al., 1994; Porter et al., 1997). Bone Morphogenetic Protein (BMP) and Fibroblast Growth Factor (FGF) signalling have been implicated in mediating some of the interactions between the optic vesicle and the future lens ectoderm to form a mature placode (Faber et al., 2001; Furuta and Hogan, 1998; Wawersik et al., 1999; for review, see Chow and Lang, 2001), but the early signals responsible for setting up the presumptive lens region remain elusive. Fig. 2. Diagram of Jacobson’s rotation experiment in amphibians (Jacobson, 1963c). When the placodal domain of an open neural plate Induction of the otic placode depends on a similarly stage embryo was rotated along its rostrocaudal axis, placodes developed complex process: early signals from the mesoderm under- according to their new position (bottom left). Occasionally an extra otic lying the placode (Gallagher et al., 1996; Ladher et al., structure was observed next to the olfactory epithelium. When the same 2000; Mendonsa and Riley, 1999; Orts-Llorca and Jimenez- experiment was performed at late neurula stages (bottom right), placode Collado, 1971) seem to act in concert with signals from the identity was already established and placodes form according to their original fate. Some variation of the results is observed probably due to the neural tube to induce otic-specific markers and the otic exact timing and position of the transplant. Note, however, that even at later vesicle. The activity of the paraxial head mesoderm seems stages, inter-placodal ectoderm is still responsive to placode inducing to be mediated by FGF signalling, however, depending on signals and additional placodes are formed close to their normal position, the species, different members of the FGF family may be for example, the olfactory placode (diagram lower right). Olfactory: orange; involved (Ladher et al., 2000; Wright and Mansour, 2003; lens: blue; otic: purple. for discussion see Riley and Phillips, 2003). A role for FGF3 as one of the major otic inducers emanating from the important features of placode induction: its multi-step hindbrain is conserved among most vertebrates, while the nature and a potentially common inducing mechanism for involvement of other FGFs expressed in the hindbrain all placode precursors. seems to vary between species (Adamska et al., 2001; Alvarez et al., 2003; Leger and Brand, 2002; Lombardo and Slack, 1998; Mansour, 1994; Maroon et al., 2002; Phillips Placode induction—a multi-step process et al., 2001; Vendrell et al., 2000; Wright and Mansour, 2003). In addition, it has been proposed that in chick Multiple inducing tissues and signals hindbrain-derived Wnt signals act synergistically with FGFs to induce the otic placode (Ladher et al., 2000), although More recent findings clearly support the idea that placode this may not be the case in zebrafish (Phillips et al., 2004). induction is a complex multi-step process. For example, lens While it is clear that otic placode formation requires FGF induction was initially believed to depend on a single signalling, loss of function approaches have shown that inductive step, in which the optic vesicle instructs the even in the absence of at least two FGFs, or even most, if overlying ectoderm to develop into the lens placode (Lewis, not all, FGF signalling, some cells retain otic marker 1904, 1907; Spemann, 1901): extirpation of the vesicle led expression and may form a rudimentary otic epithelium to failure of lens formation, while its ectopic transplantation (Liu et al., 2003; Maroon et al., 2002; Phillips et al., 2001; appeared to induce lens from belly ectoderm. However, Wright and Mansour, 2003). This raises the possibility that soon thereafter conflicting evidence was obtained, showing additional upstream signals initiating otic development normal lens formation in the absence of the optic vesicle remain to be identified. (King, 1905; Mencl, 1903), and other tissues were In contrast, it has been suggested that the trigeminal and implicated in lens induction (Henry and Grainger, 1987; epibranchial placodes giving rise to cranial ganglia require Jacobson, 1958; Liedke, 1942, 1951, 1955). Recent studies less complexity of inductive interactions or signals. One or using molecular markers and labelling techniques to identify more unknown signal(s) from the neural tube (no other graft and host tissues unequivocally suggest that indeed, tissues being required) promote the formation of the early lens induction depends on signals from both the ophthalmic part of the trigeminal placode (Stark et al., A. Streit / Developmental Biology 276 (2004) 1–15 5

1997), and epibranchial placodes are generated through an transcription factors can initiate placode formation, they can interaction with pharyngeal endoderm, where it comes into only do so near cells that normally give rise to placodes, contact with the ectoderm just dorsal to the branchial clefts namely within the pre-placodal region. (Begbie et al., 1999). This endoderm expresses high levels In summary, the findings described above strongly of BMP7, and this factor can induce neuronal markers support the notion that formation of mature placodes is a characteristic of epibranchial placodes in isolated, non- multi-step process where different tissues and signals act epibranchial ectoderm, whereas inhibition of BMP signal- sequentially and/or cooperatively. So far, no experimental ling results in the loss of epibranchial neurons. Thus, BMP7 manipulation has yet led to the induction of placodes away is clearly involved in some step of epibranchial placode from their normal position, in ectoderm that does not specification. However, there is one caveat in interpreting normally contain placode precursors. Therefore, it is likely both experiments: the test tissue used to assay placode that some of the upstream signals that initiate placode induction is ectoderm either fated to become the same formation remain to be identified. Could one of the placode or ectoderm containing precursors for other upstream steps involve the formation of a pre-placodal placodes. It is therefore possible that these tissues had domain as suggested by Jacobson? already received other signals at the time of their isolation, which may have established a placodal bias. The pre-placodal region is defined by cell fates and Placode-specific transcription factors can only induce unique gene expression ectopic placodes within the pre-placodal domain The existence of a pre-placodal region implies that all While the studies summarised above focused on the placodal precursors arise from a continuous domain of the inducing signals and tissues, functional analysis of the embryonic ectoderm. Many of the fate map studies that transcription factors that integrate these signals within the localised future placodes to the ectoderm and outer neural placode have revealed similar levels of complexity. A large folds in the head have been performed after neurula stages number of transcription factors, among them members of when precursors for different placodes begin to be confined the Sox, Dlx, Fox and Pax gene families, have been to unique regions (Fig. 1A; Carpenter, 1937; Couly and Le identified that are expressed in one or more placodes (for Douarin, 1985, 1987, 1988; D’Amico-Martel and Noden, review see Baker and Bronner-Fraser, 2001). While loss-of- 1983; Rfhlich, 1931; for review, see Baker and Bronner- function approaches have clearly demonstrated that some of Fraser, 2001). A recent study in zebrafish shows a continuous these genes are essential for placode formation, so far gain- domain of placode precursors adjacent to the future brain at of-function experiments have failed to identify any factor gastrula stages (Kozlowski et al., 1997), while lineage sufficient to make non-placodal ectoderm (future epidermis) studies in the chick have identified a unique region of the acquire placodal characteristics. embryonic ectoderm that contains precursors for most, if not The two homeobox genes, Pax6 and Six3, are necessary all, placodes abutting the anterior neural plate slightly later for normal vertebrate eye and lens development (Carl et al., (Bhattacharyya et al., 2004; Streit, 2002; Fig. 3). In this 2002; Collinson et al., 2000, 2003; Grindley et al., 1997; territory, precursors for different placodes are intermingled Hogan et al., 1986; Lagutin et al., 2003; Quinn et al., 1996; and are recruited from a large area to their final position Wallis and Muenke, 1999; for review, see: Cvekl and (Bhattacharyya et al., 2004; Streit, 2002; Whitlock and Piatigorsky, 1996; Gehring and Ikeo, 1999; Kawakami et Westerfield, 2000). These studies first identify the pre- al., 2000; Oliver and Gruss, 1997). Overexpression of either placodal region at early neurula stages surrounding the neural factor results in ectopic lenses, which are, however, always plate from forebrain to hindbrain levels, reminiscent of the associated with neural structures (either ectopic retinae or a bprimitive placodal thickeningQ observed in mouse, fish and lens that develops very close to the host neural tube; some amphibians and of Jacobson’s bplacodal fieldQ. While Altmann et al., 1997; Chow et al., 1999; Lagutin et al., fate map studies cannot resolve the question of whether or 2001; Oliver et al., 1996). Expression of Six3 under the not different placodes share some inductive events, the fact control of regulatory elements that drive Pax2 expression in that their precursors initially overlap considerably is con- the otic territory leads to ectopic Pax6 expression in the sistent with the notion of a pre-placodal region. placode (Lagutin et al., 2001). Likewise, misexpression of If a common placode territory indeed exists, it should be the HMG-box factor Sox3 results in the formation of ectopic characterised not only by the position of relevant precursors, vesicles that express Pax6, but only next to endogenous but also by unique properties, like expression of a specific placodes (Koster et al., 2000). One of the earliest genes set of molecular markers that distinguish it from other expressed in the otic territory is the forkhead gene foxi1;itis regions of the ectoderm. Indeed, at neurula stages, members required for otic induction and can induce ectopic expres- of several gene families begin to be expressed or are up- sion of the otic marker Pax8 in a spatially restricted manner regulated in a horseshoe-shaped area encircling the anterior next to the neural tube, but not in ventral ectoderm (Nissen neural plate among them Six, Eya, Id, Dlx, Iro and Fox et al., 2003; Solomon et al., 2003a). Thus, while some genes (Akimenko et al., 1994; Esteve and Bovolenta, 1999; 6 A. Streit / Developmental Biology 276 (2004) 1–15

Fig. 3. Placode precursors at mid-gastrula and early neurula stages. (A) In zebrafish, placode precursors are found in the ectoderm adjacent to the future central nervous system (grey) from fore- to hindbrain level. Precursors for different placodes partially overlap, but are roughly organised according to their later position along the rostrocaudal axis. Vermillion: lens and olfactory placode, telencephalon; pale yellow: lens, olfactory epithelium, anterior cranial ganglia, otic vesicle, telencephalon; green: otic vesicle, posterior lateral line; dark grey: caudal lateral line; modified according to (Kozlowski et al., 1997); CNS fate map after (Woo and Fraser, 1995). (B) At the 0–1 somite stage in the chick, precursors for different placodes are intermingled in a horseshoe-shaped domain encircling the neural plate. Their posterior limit lies at the level of Hensen’s node adjacent to cells that will contribute to rhombomeres 6–7. Olfactory: orange; lens: blue; otic: purple; epibranchial: dark blue. Note: complete maps for epibranchial and trigeminal precursors are not available. Modified after Bhattacharyya et al. (2004) and Streit (2002).

Kee and Bronner-Fraser, 2001a,b; Liu and Harland, 2003; Thus, the position of placode precursors is demarcated by Luo et al., 2001a,b; McLarren et al., 2003; Mishima and co-expression of a specific set of genes in a continuous Tomarev, 1998; Nissen et al., 2003; Ohyama and Groves, domain surrounding the rostral neural plate, strongly 2004; Pandur and Moody, 2000; Papalopulu and Kintner, supporting the idea that different placodes initially share a 1993; Pera et al., 1999; Sahly et al., 1999; Schlosser and developmental programme. It is conceivable that cells Ahrens, 2004; Solomon and Fritz, 2002; Solomon et al., within this region have received signals to bias them 2003b; Streit, 2002; Wilson and Mohun, 1995). Some of towards a placodal fate, which in turn may account for the them, like Dlx genes, are not uniquely found in placodal fact that induction of ectopic placodes has so far only been cells but also encompass other ectodermal derivatives like achieved close to their normal position (see above). The future epidermis and/or neural crest. In contrast, Six and Eya precise function of Six and Eya proteins during these gene expression domains most closely reflect the location of processes is still unclear, however, it is possible that they placode precursors (compare Figs. 3 and 4) and members of specify cells as placodal without conferring placodal both families have been described in comparable patterns in identity. While several studies have addressed specification chick, fish and amphibian embryos (Esteve and Bovolenta, of individual placodes, we know nothing about the 1999; McLarren et al., 2003; Mishima and Tomarev, 1998; developmental state of pre-placodal cells. However, it is Pandur and Moody, 2000; Sahly et al., 1999; Schlosser and clear that this territory is unique due to its restriction to Ahrens, 2004; Streit, 2002). Although Xenopus fate map specific cell fates, its special properties and the expression data for the non-neural ectoderm at this stage are not of a unique set of molecular markers. available, a comparative expression analysis of placodal transcription factors relative to those found in neural and neural crest ectoderm supports the notion that Six and Eya The Six/Eya/Dach network in the pre-placodal region genes may represent pre-placodal markers (Schlosser and Ahrens, 2004). During later development, most of the genes Among the many genes expressed in the pre-placodal present in the placodal territory are either lost completely region, the expression of members of the Six and Eya from placodal tissue, maintained in only some placodes families most closely mirrors the cellular changes during (e.g., Fox) or down-regulated before re-appearing later in placode formation. Their Drosophila homologues, sine some mature placodes (e.g., Dlx). In contrast, mimicking oculis (so) and eyes absent (eya), form a regulatory network morphological changes of the ectoderm during placode that, together with the nuclear factor dachshund (dac), formation (see above), Six and Eya are the only transcripts controls specification of sensory structures, namely photo- to be maintained in all developing placodes, while being lost receptor cells (Bonini et al., 1993, 1997; Chen et al., 1997; Li from inter-placodal domains. et al., 2003; Mardon et al., 1994; Pignoni et al., 1997; Shen A. Streit / Developmental Biology 276 (2004) 1–15 7

Fig. 4. Expression of pre-placodal markers. Whole mount in situ hybridisation of 3–5 somite chick embryos using Six1 (A, aV), Eya2 (B, bV) and Dach1 (C, cV) antisense probes. Six1 (A, aV) and Eya2 (B, bV) expression in the ectoderm is confined to a domain surrounding the neural plate (np) from its most anterior edge to approximately node levels (arrow in A–C). This region corresponds to the position of placodal precursors, the pre-placodal domain (ppr; see Fig. 3). In contrast, Dach1 transcripts (C, cV) are distributed more widespread and found in the neural plate (np) as well as the pre-placodal domain (ppr), where they overlap with Six1 and Eya2. and Mardon, 1997; for review, see: Kumar and Moses, display inner ear abnormalities similar to the defects 2001c). Mutations in any of these genes leads to absence or observed in Eya1À/À mice: the otic vesicle fails to grow reduction of the Drosophila eye, while their overexpression and the cochlear duct and/or semicircular canals are absent can induce ectopic eye formation in a spatially restricted (Laclef et al., 2003; Li et al., 2003; Zheng et al., 2003). Like manner (Bonini et al., 1993; Mardon et al., 1994; Pignoni Eya1 mutant mice, Six1À/À mice lack both the cochlear– et al., 1997). In vertebrates, members of these families are not vestibular and petrosal ganglia. only expressed in the pre-placodal domain, but also later in However, a complete loss of placodal derivatives in any different combinations in each of the mature sensory of the mutants generated has not been observed as one placodes and some of their derivatives (for review, see might have expected if these genes were instrumental in Hanson, 2001; Kawakami et al., 2000). For example, while defining the pre-placodal domain. Since several members Eya1, Six1, Six4 and Dach1 are found in parts of the otic of the Six and Eya families are co-expressed in this region vesicle, the olfactory placode expresses Eya2, Six1 and Six3 and seem to share functional properties, the lack of an (Bovolenta et al., 1998; Davis et al., 1999; Ghanbari et al., early phenotype may be due to functional redundancy. 2001; Heanue et al., 2002; Mishima and Tomarev, 1998; There is good evidence that Six, Eya and Dac proteins Oliver et al., 1995; Pandur and Moody, 2000; Xu et al., form a regulatory network and that they interact physically 1997). to activate downstream target genes. In Drosophila, so, eya In addition, loss-of-function analysis has revealed an and dac expression is interdependent, while their combined important role for Six and Eya proteins in ear, eye and nasal misexpression in imaginal discs other than the eye disc development. Mice heterozygous for Eya1 show a con- shows strong synergistic effects with a dramatically ductive loss of hearing due to defects of the middle ear (Xu increased frequency of ectopic eye induction (Chen et al., et al., 1999), a condition very similar to the human 1997; Mardon et al., 1994; Pignoni et al., 1997; Shen and Branchio-Oto-Renal syndrome caused by a mutation in Mardon, 1997). Although the interdependence of gene the EYA1 gene (Abdelhak et al., 1997). Homozygous expression in vertebrates is not always conserved (Heanue Eya1À/À mice display severe inner ear defects: otic placode et al., 2002; Zheng et al., 2003; for review see: Hanson, formation is initiated normally but development arrests at 2001; Wawersik and Maas, 2000), the only case where the vesicle stage and the cochlear–vestibular ganglia do not compound homozygous mutations have been generated in form (Xu et al., 1999). In addition, the epibranchial placode mice, namely for Six1 and Eya1, shows a more severe ear derived petrosal ganglia are missing. Mutations in the phenotype than each mutation separately (Li et al., 2003; human EYA1 gene also lead to congenital eye defects Zheng et al., 2003), supporting the idea that they may act in (Azuma et al., 2000), however, the eye phenotypes in mice a molecular network and synergise with each other. In have been less well studied. Mice lacking Six1 function addition, in vitro studies have clearly demonstrated a 8 A. Streit / Developmental Biology 276 (2004) 1–15 physical interaction between Six and Eya as well as Dach has been conserved in vertebrates to regulate sensory organ and Eya proteins (Chen et al., 1997; Ikeda et al., 2002; Li development at different levels. et al., 2003; Ohto et al., 1999; Silver et al., 2003). While Six1 alone or Six1/Dach seems to act as transcriptional repressors, Eya recruits co-activators; due to their phospha- Signals and tissues mediating the induction of the tase activity, Eya proteins stabilise co-activator interactions pre-placodal domain and switch the complex to activate downstream target genes (Li et al., 2003). Thus, co-expression of Six, Eya and Dach How is the pre-placodal region established in the family members in the pre-placodal domain may be func- ectoderm adjacent to the rostral neural plate? As mentioned tionally significant and their role will need to be addressed at the beginning of this review, studies in amphibian in the future. embryos have implicated the endoderm, the presumptive In the Drosophila eye, the Six/Eya/Dach network heart mesoderm and the neural plate as early placode functions downstream of the Pax6 homologue eyeless inducing tissues, which may act in combination or (ey), while in other embryonic tissues, their expression is sequentially. Neither mesoderm nor endoderm alone, how- independent of Pax genes (Bonini et al., 1997; Halder et ever, appears to be sufficient to trigger the development of a al., 1998; Kumar and Moses, 2001b; Niimi et al., 1999). complete ear or lens vesicle or a nasal sac. Signals emitted Interestingly, during vertebrate placode development, Pax by these tissues may be responsible for setting up the initial gene expression (with the exception of Pax6 in the lens- common placodal field. olfactory domain; Bhattacharyya et al., 2004; Li et al., Neural crest cells arise at the border of the neural plate in 1994) is only initiated once placodes with characteristic close association with future placodes. Interaction of the identity begin to be specified. While Pax6 identifies the neural plate with future epidermis is sufficient to induce lens and later the olfactory placode (Grindley et al., 1995; neural crest at the interface (Dickinson et al., 1995; Mancilla Li et al., 1997; Nornes et al., 1998; Schlosser and Ahrens, and Mayor, 1996; Moury and Jacobson, 1990; Selleck and 2004; Walther and Gruss, 1991), Pax2 is specific for the Bronner-Fraser, 1995) and both Wnt and BMP pathways otic and epibranchial (Groves and Bronner-Fraser, 2000; have been implicated in this process (for review, see: Aybar Heller and Brandli, 1999; Krauss et al., 1991; Pfeffer et al., and Mayor, 2002; Knecht and Bronner-Fraser, 2002; 1998; Schlosser and Ahrens, 2004) and Pax3 for the LaBonne, 2002; Mayor and Aybar, 2001; Nieto, 2001; trigeminal placode (Stark et al., 1997). So far none of the Yanfeng et al., 2003). Are the same tissue interactions and Pax genes seems to be expressed in the lateral line signalling pathways responsible for placode induction? In placodes of amphibians and fish embryos (Schlosser and Drosophila, the expression of so, eya and dac during eye Ahrens, 2004). It is therefore tempting to speculate that the development is dependent on the presence of the BMP expression of members of the Six/Eya/Dach network in the homologue decapentaplegic (dpp) (Chen et al., 1999; Curtiss pre-placodal domain assembles some of the molecular and Mlodzik, 2000), while in the leg imaginal disc dac is network required for placode formation, but is not induced by a combination of dpp and the Wnt homologue sufficient by itself to complete the developmental pro- wingless (Wg) (Lecuit and Cohen, 1997). It will be gramme. In this scenario, Pax gene expression may initiate interesting to investigate whether similar upstream signalling the formation of a placode proper and together with other pathways control pre-placodal gene expression. Some transcription factors confer placode identity. Thus, one support for this idea comes from the finding that BMPs potential role of the Six/Eya/Dach network is to bestow participate in patterning the ectoderm during or shortly after placodal competence or bias to the ectoderm next to the gastrulation (for review, see: Mayor and Aybar, 2001; Sasai anterior neural plate. and De Robertis, 1997; Wilson and Hemmati-Brivanlou, A quite different possibility, however, is that the Six/Eya/ 1997). BMPs are thought to act as a morphogen gradient to Dach network is involved in regulating proliferation of pre- specify different cell types at distinct concentrations: high placodal cells. Loss-of-function alleles of so, eya and dac in levels of BMP activity promote the formation of epidermis, Drosophila produce a transient overgrowth within the eye intermediate levels the formation of neural crest, while low field, followed by extensive cell death resulting in reduction or no BMP signalling allows neural development (Barth or loss of the eye. In vertebrates, in vivo and in vitro data et al., 1999; Nguyen et al., 1998, 2000; Tribulo et al., 2003; suggest that lack of functional Six1, Eya2 or Eya3 leads to Wilson et al., 1997). A recent study revealed that expression reduced proliferation (Li et al., 2003; Pignoni et al., 1997; of the homeodomain protein Iro1, which labels the pre- Zheng et al., 2003). As a consequence, Six1 as well as Eya1 placodal region, is regulated by BMP (Glavic et al., 2004). mutant mice show severe inner ear phenotypes displaying However, the formation of olfactory and otic placodes is small otic vesicles that lack several otic placode-derived differentially affected in zebrafish mutants that show structures or cell types. moderate or severe disruption of the BMP signalling Regardless of the precise molecular function of the Six/ pathway (Nguyen et al., 1998), making it unlikely that a Eya/Dach network, it is remarkable that the same molecular unique threshold of BMP defines the placode territory. cassette used in Drosophila to specify photoreceptor cells Future studies will be necessary to unravel the signalling A. Streit / Developmental Biology 276 (2004) 1–15 9 pathways that specify the pre-placodal region and to these movements are random and that only cells that determine how these are integrated with signalling mecha- encounter placode-specific inducing signals from surround- nism that define the position of individual placodes. ing tissues are directed towards a specific fate. Alternatively, individual cells or groups of cells may already have acquired specific identities and according to these properties Transcription factor codes for different ectodermal move directionally to their final destination, sorting out domains? from their neighbours. Interestingly, some placode-specific genes like the otic marker Pax2 begin to be expressed in a One important question that remains open is how salt-and-pepper pattern (Streit, 2002). Thus, mosaic gene ectodermal patterning signals are interpreted by individual expression may reflect differential properties of individual cells to implement cell fate decisions. Some of the earliest cells in the pre-placodal territory. It will be necessary in the patterning events appear to begin before gastrulation, as future to investigate whether directional cues guide these indicated by the complex domains of gene expression in the precursors to their target position in the mature placode and ectoderm. Evidence from the chick suggests that before the degree to which these mosaic patterns of expression primitive streak formation the ectoderm is subdivided into might reflect differential competence to inducing signals, or two domains revealed by the mutually exclusive expression different states of commitment and differential responsive- of Sox3 and ERNI in one (Streit et al., 2000) and low levels ness to chemoattractants and/or repellents, or cell sorting of Msx1 (Streit and Stern, 1999), Dlx5 (Pera et al., 1999) mechanisms that would guide them to their appropriate and Gata2 and -3 (Sheng and Stern, 1999) in the other. destinations. Concomitant with the onset of expression of stable neural markers, like Sox2, in the future neural plate, Msx1 and the early neural crest marker Pax7 are up-regulated along its Parallels between fly and vertebrates: determination of border in a fairly broad stripe of cells. At the same time, pre- placode and imaginal disc identity placodal gene expression starts in the ectoderm lateral to the neural plate, overlapping medially with Msx1 and Pax7 Although vertebrate sensory placodes have no direct (Streit and Stern, 1999; Litsiou and Streit, unpublished structural or functional homologues in Drosophila and are observations). Shortly thereafter, however, early crest and unlikely to have evolved directly from sensory organs in the placodal markers are restricted to distinct regions of the fly, some of the molecular cassettes that regulate the ectoderm: Msx1 and Pax7 are confined to the neural folds development of such organs in both groups are surprisingly abutting Sox2 medially and Six1, Six4 and Eya2 laterally well conserved. The idea of a common domain for sensory (McLarren et al., 2003; Schlosser and Ahrens, 2004; Streit, placode precursors is remarkably similar to the situation in 2002). The successive restriction of transcription factors to Drosophila, where light, odour and sound perceiving cells distinct ectodermal domains may reflect the specification of arise from a common primordium, the eye-antennal disc. In different cell fates within the embryonic ectoderm. In the adult, photoreceptor cells are confined to the compound addition, these observations may point to negative as well eye, while the antenna contains cells with both auditory and as positive regulatory relationships between different tran- chemosensory function. Precursors for these cells arise from scription factors, which cooperate to integrate ectodermal the eye-antennal disc, a small group of epithelial cells that is patterning signals on a cell-by-cell basis. set aside during early development. During larval development eye and antennal precursors segregate until two separate entities are established that have distinct identities: Cell movements within the pre-placodal domain the eye and the antennal primordium. Some of the key regulators that confer identity to these primordia are the Once the pre-placodal domain is established, how do transcription factors distalless and eyeless (Cohen et al., precursors for individual placodes acquire distinct properties 1989; Dong et al., 2000; Halder et al., 1995, 1998; Sunkel and become different from each other? Within the pre- and Whittle, 1987; for review, see Gehring, 1996; Panga- placodal ectoderm, precursors for different placodes are niban and Rubenstein, 2002). Both proteins are initially co- initially interspersed (Bhattacharyya et al., 2004; Kozlowski expressed, but subsequently separate with eyeless being et al., 1997; Streit, 2002). Precursors for specific placodes confined to the eye primordium, while distalless is found in are recruited from a large area within this territory and the antennal part (Kumar and Moses, 2001a,b). It has been converge to their final position. Recent studies both in suggested that both transcription factors negatively cross zebrafish and chick suggest that they do so by extensive cell regulate each other to establish eye versus antennal cell fates movements while constantly changing their neighbours and (Kurata et al., 2000). Interestingly, a similar molecular undergoing cell rearrangements (Streit, 2002; Whitlock and mechanism may be involved in conferring lens versus Westerfield, 2000). In the chick, groups of cells from a olfactory placode identity in vertebrates. It is well estab- single location ultimately contribute to different placodes. lished that the vertebrate eyeless homologue, Pax6, is How is their segregation controlled? One possibility is that required in the presumptive lens ectoderm for development 10 A. Streit / Developmental Biology 276 (2004) 1–15 of a normal lens placode and a functional lens (Ashery- Precursors for different placodes arise from a common pre- Padan et al., 2000; for review, see Ashery-Padan and Gruss, placodal region characterised by the expression of a unique 2001; Callaerts et al., 1997; Gehring, 2002). Before placode set of molecular markers and by unique cellular properties. formation, however, Pax6 is expressed in the anterior Future studies will have to investigate the upstream signals ectoderm encircling the future forebrain—a region of the that establish the pre-placodal region as well as the role of ectoderm that contains cells fated to become lens and transcription factor networks implementing cell fate deci- olfactory placode (Bhattacharyya et al., 2004; Li et al., sions within this region. Molecular networks that govern 1994). Interestingly, the distalless homologue Dlx5 initially sensory organ formation in insects are remarkably con- colocalises with Pax6 in the ectoderm, however, as soon as served in vertebrates and may be used repeatedly to control the lens placode forms a columnar epithelium, Dlx protein is specification of the pre-placodal field, placode identity as lost form this territory, while Pax6 expression is maintained well as cell type specification within placodes. (Bhattacharyya et al., 2004). When lens precursors are forced to maintain Dlx5 beyond this time, they become excluded from the lens, cluster in the non-lens ectoderm and Acknowledgments acquire lens-specific gene expression (Bhattacharyya et al., 2004). These data suggest that the loss of Dlx protein is I am grateful to Claudio D. Stern for critical reading of required for cells to acquire lens identity in a process that the manuscript and would like to thank the anonymous parallels molecular events that lead to the manifestation of reviewers for their particularly constructive comments. imaginal disc identity in the fly. What is the cellular mechanism underlying this behav- iour? Like Dlx5 maintaining lens precursors, Pax6À/À cells References in mouse chimaeras are excluded from the lens territory (Collinson et al., 2000), suggesting that Pax6 expression Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Weil, D., Cruaud, C., Sahly, I., Leibovici, M., Bitner-Glindzicz, M., confers cells with adhesive properties different from their Francis, M., Lacombe, D., Vigneron, J., Charachon, R., Boven, K., neighbours. Similarly, in the leg imaginal disc of Droso- Bedbeder, P., Van Regemorter, N., Weissenbach, J., Petit, C., 1997. 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