Integrative and Comparative Biology Advance Access originally published online on May 22, 2007
Integrative and Comparative Biology 2007 47(3):343-359; doi:10.1093/icb/icm031
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How old genes make a new head: redeployment of Six and Eya genes during the evolution of vertebrate cranial placodes
Brain Research Institute, University of Bremen, FB2, PO Box 330440, 28334 Bremen, Germany
Correspondence: 1E-mail: gschloss{at}uni-bremen.de
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 Synopsis IntroductionDevelopment of vertebrate...Induction of Six and...Promotion of placodal...Evolutionary origin of the...References |
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Cranial placodes give rise to many evolutionary novelties of the vertebrate head, such as its specialized paired sense organs and cranial ganglia. There is an increasing evidence that all placodes originate from a common primordium located around the anterior neural plate and defined by the expression of transcription factors of the Six1/2, Six4/5, and Eya families. These transcription factors continue to be expressed in the different placodes and appear to control similar developmental processes (e.g., proliferation, cell shape changes, and neurogenesis) in the different placodes suggesting that they play a central role for generic placodal development. Elucidating the central role of Six and Eya genes for placodal development requires an understanding of (1) how these genes are induced in the pre-placodal ectoderm at the right place and time and (2) how they subsequently affect and promote placodal development. The first part of this review gives a brief overview of what is currently known about these upstream and downstream regulatory linkages of Six and Eya genes. The second part of the review then discusses the distribution and function of Six and Eya genes in other deuterostomes in order to infer changes of upstream and downstream linkages in the course of deuterostome evolution by which Six and Eya genes adopted their new role in vertebrate placode development. It is argued that these genes were probably recruited to the neural plate border in the ancestor of urochordates and vertebrates, and adopted novel roles in the regulation of neuronal differentiation and possibly other pathways of cytodifferentiation as well in the vertebrate lineage.
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Introduction |
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SynopsisIntroductionDevelopment of vertebrate...Induction of Six and...Promotion of placodal...Evolutionary origin of the...References |
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One of the most distinct features of vertebrates is their elaborate head with a complex brain encased in a cartilaginous or bony skull and equipped with sophisticated paired sense organs including nose, eyes, and ears. These specializations of the head are absent in other chordates and represent evolutionary innovations of vertebrates. More than 20 years ago, Northcutt and Gans suggested that the special features of the vertebrate head (i.e., the "new head" of vertebrates) evolved concomitant with the adoption of a predatory lifestyle in the vertebrate lineage (Gans and Northcutt 1983
; Northcutt and Gans 1983; Northcutt 2005). They also pointed out that many of the new characters of the vertebrate head develop from only two novel embryonic tissues, which appeared in the vertebrate lineage, viz. the neural crest and cranial placodes.
When and how precisely neural crest and cranial placodes originated during vertebrate evolution is still poorly understood. However, our understanding of the molecular and cellular basis of neural crest and placode development in vertebrates has made great strides in the past decades (reviewed by Baker and Bronner-Fraser 2001; Knecht and Bronner-Fraser 2002; Morales et al. 2005; Steventon et al. 2005; Bailey and Streit 2006; Schlosser 2006). Many cellular interactions, transcription factors, and signaling molecules that are crucially involved in the development of the neural crest and placodes have now been identified. These insights are increasingly employed to investigate whether homologous molecules or cell types in protochordates (i.e., urochordates and cephalochordates) or other deuterostomes (e.g., hemichordates, echinoderms) engage in similar interactions in order to identify evolutionary precursors of neural crest cells and placodes and ideally to elucidate sequences of regulatory changes that led to the origin of these novel vertebrate tissues (reviewed in Holland and Holland 2001; Holland et al. 2004; Meulemans and Bronner-Fraser 2004; Holland 2005; Schlosser 2005; Barrallo-Gimeno and Nieto 2006; Sauka-Spengler and Bronner-Fraser 2006).
In this review I will concentrate on the evolutionary origin of placodes. I will specifically focus on two classes of transcription factors encoded by the Six and Eya genes, which play central roles in the development of vertebrate placodes and will discuss, how they may have adopted these roles by stepwise modification of their ancestral functions (for a more comprehensive review of placode evolution, see Schlosser 2005). I will first briefly introduce cranial placodes and sketch how their development is regulated by different transcription factors including those encoded by Six and Eya genes. I will then discuss the upstream and downstream developmental processes which put these transcription factors center-stage in placodal development: first, how are these genes activated in a spatiotemporally appropriate manner during the earliest stages of placodal development and second, how do they drive multiple developmental processes crucial for placode development? Finally, I will compare vertebrates with other deuterostomes and discuss possible scenarios for evolutionary changes in the regulation and function of Six and Eya genes during the origin of placodes.
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Development of vertebrate cranial placodes |
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SynopsisIntroductionDevelopment of vertebrate...Induction of Six and...Promotion of placodal...Evolutionary origin of the...References |
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Placodes are specialized regions of the embryonic ectoderm that give rise to a variety of nonepidermal cell-types. Often but not always placodes are recognizable as local thickenings of the ectoderm. The cranial placodes as considered here comprise the adenohypophyseal placode, olfactory placode, lens placode, otic placode, a series of lateral line placodes, the profundal and trigeminal placodes, and a series of epibranchial placodes (Fig. 1B). Lateral line placodes have been secondarily lost in a number of vertebrates including amniotes.
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The various placodes differ in position, mode of development, and derivative cell types from each other (for details and references, see reviews of Webb and Noden 1993
; Baker and Bronner-Fraser 2001; Schlosser 2005, 2006; Bailey and Streit 2006). The adenohypophyseal placode develops into the anterior pituitary with six types of neurosecretory cells involved in hormonal control of growth, reproduction, and other important bodily functions. The olfactory placode gives rise to the epithelium of the nose with its olfactory and vomeronasal sensory cells. These are primary sensory cells that form axons constituting the olfactory and vomeronasal nerves. In addition, the olfactory placode also gives rise to cells that migrate away from the placode and into the forebrain including glia cells and cells producing neuropeptides such as gonadotropin releasing hormone (GnRH). The lens placode develops into the lens of the eye composed of cells rendered transparent by the accumulation of various crystallin proteins. The otic placode gives rise to the entire inner ear, including the hair cells and supporting cells of its auditory and vestibular sensory areas. Hair cells are secondary sensory cells that do not possess an axon. They are innervated by sensory neurons of the vestibulocochlear ganglion, which are also derived from the otic placode. Similarly, lateral line placodes give rise to the mechanosensory and electrosensory receptor organs of the lateral line system, likewise composed of hair cells and supporting cells, as well as to the sensory neurons of the lateral line ganglia, which innervate these receptors, thereby forming the lateral line nerves. Profundal and trigeminal placodes as well as the epibranchial placodes contribute sensory neurons to the ganglia of the profundal and trigeminal, facial, glossopharyngeal, and vagal cranial nerves; another subpopulation of sensory neurons in these cranial ganglia is derived from the neural crest. Despite these differences in fates, there are some generic aspects of placode development shared by the different placodes. In particular, placodals cells tend to undergo various cell shape changes during their development, for example, during the establishment of placodal thickenings, the invagination of placodes (in the adenohypophyseal, olfactory, lens, and otic placodes), or the migration of glia, neurosecretory or neuronal cells away from the placodes (in all except the lens placodes). Moreover, with exception of the adenohypophyseal and lens placodes, all placodes are neurogenic, i.e., they all include neurons among their derivative cell types.
Recently it was proposed that these generic aspects of placode development are not merely due to superficial similarities but rather reflect a common developmental program shared by all placodes (Torres and Giráldez 1998; Baker and Bronner-Fraser 2001; Streit 2004; Schlosser and Ahrens 2004; Schlosser 2005, 2006; for a different view, see Graham and Begbie 2000; Begbie and Graham 2001). This hypothesis is supported by the conjunction of two lines of evidence. First, fate maps from many different vertebrates show that the different placodes all originate from a common precursor region (preplacodal region) located around the anterior neural plate in the outer neural folds and adjacent ectoderm (Carpenter, 1937; Kozlowski et al. 1997; Streit 2002; Bhattacharyya et al. 2004). Second, this precursor region is already biassed for generic placodal development and, therefore, indeed represents a common primordium for all placodes (panplacodal primordium). This is suggested by its expression of a number of transcription factors (Fig. 1A, C, and D), which are later maintained in all or multiple placodes and regulate various aspects of their development (reviewed by Schlosser 2006). Moreover, ectoderm from the preplacodal region is predisposed to adopt some kind of placodal fate as revealed by transplantation experiments in different vertebrates. They show that compared to other types of ectoderm (e.g., prospective epidermal ectoderm), ectoderm from various parts of the preplacodal region more readily adopts a particular placodal fate (e.g., otic placode), when transplanted into the territory of that placode, or when exposed to localized signals required for its induction (reviewed by Streit 2004; Bailey and Streit 2006; Schlosser 2006). Most clearly, this has recently been demonstrated in chick embryos, where only ectoderm from within but not from outside the preplacodal region was able to express markers of the otic placode in response to fibroblast growth factors (FGFs) that serve as otic inducers (Martin and Groves 2006). Other recent experiments in the chick have shown that ectoderm throughout the preplacodal region but not outside of it will develop into lens tissue unless they are exposed to additional signals (Bailey et al. 2006). This indicates that initially there is indeed a common placodal ground state shared throughout the preplacodal ectoderm, before its various subregions diverge to become different placodes.
As already mentioned, the preplacodal region expresses a number of transcription factors that are later maintained in placodes. Many of these transcription factors are only expressed in subregions of the preplacodal region or are expressed in other regions of the ectoderm as well and are, therefore, unlikely to be specifically dedicated to the promotion of generic placodal properties (reviewed by Schlosser 2006). Ectodermal expression of a small number of transcription factors, however, is largely confined to the preplacodal region and covers its entire extent, most notably transcription factors of the Six and Eya families, homologues of the Drosophila sine oculis and eyes absent genes, respectively (Fig. 1A, C, and D). The expression patterns and molecular interactions of these genes have been extensively reviewed elsewhere (Kawakami et al. 2000; Pappu and Mardon 2004; Streit 2004; Silver and Rebay 2005; Rebay et al. 2005; Schlosser 2005, 2006) and, thus, are only briefly summarized here.
There are typically four members of the Eya family in vertebrates (Eya1–4), whereas there are three subfamilies of Six genes (Six1/2, Six4/5, Six3/6), with typically two members each in vertebrates. The expression patterns of the various Eya and Six genes differ slightly between different vertebrates, but generally at least some of the Eya genes and of the Six1/2 and Six4/5 subfamily genes are initially expressed in the preplacodal region and later maintained in various placodes (Schlosser and Ahrens 2004). Six3/6 subfamily genes have a different pattern of expression (in anterior parts of the preplacodal region and the anterior neural plate). Whereas Six genes encode transcription factors with direct DNA-binding capacity, Eya genes encode proteins that affect transcription indirectly by binding to other proteins. In particular, Eya proteins are known to directly interact with Six transcription factors and with a number of other proteins (such as Dach) in a common transcriptional complex (Pignoni et al. 1997; Ohto et al. 1999; Ikeda et al. 2002; Li et al. 2003). Six, Eya, and Dach genes also engage in cross-regulatory interactions with each other and with Pax genes. The presence of some sort of genetic interaction between Pax, Six, Eya, and Dach genes appears to be evolutionarily conserved in bilaterians, but the details of the network differ between different expression domains and different taxa (reviewed by Relaix and Buckingham 1999; Hanson 2001; Donner and Maas 2004; Silver and Rebay 2005).
Mutants of Eya1 and Six1 genes are known from humans, mice, and zebrafish and they generally show a very similar spectrum of deficiencies reflecting their coexpression and synergistic function in different tissues. Most notably, Eya1 and Six1 mutants exhibit a wide gamut of deficiencies in various placodes (reviewed in more detail subsequently), suggesting that they are important regulators of placodal development. Since they particularly seem to affect developmental processes such as cell proliferation, apoptosis, morphogenesis, and neurogenesis, which play a role during the development of most if not all placodes, and are widely expressed in different placodes, they are currently the most promising candidates for genes involved in promoting generic placodal properties in vertebrates. In order to elucidate this putative central role of Six and Eya genes for placodal development, we have to understand on the one hand how these genes are induced in the preplacodal ectoderm at the right place and time, and on the other hand, how Six and Eya genes affect and promote placodal development. The next two sections review this in turn, before the final section discusses how these upstream and downstream regulatory linkages may have originated during deuterostome evolution.
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Induction of Six and Eya genes in pre-placodal ectoderm |
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SynopsisIntroductionDevelopment of vertebrate...Induction of Six and...Promotion of placodal...Evolutionary origin of the...References |
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Eya genes and Six1/2 and Six4/5 subfamily genes (henceforth referred to as panplacodal genes) are induced at early neural-plate stages in the preplacodal region. The tissues and signals responsible for their induction have been investigated in chick and Xenopus embryos (McLarren et al. 2003
; Woda et al. 2003; Brugmann et al. 2004; Glavic et al. 2004; Ahrens and Schlosser 2005; Litsiou et al. 2005). Both the dorsolateral endomesoderm underlying the preplacodal ectoderm and the anterior neural plate adjacent to it were shown to be required for the induction of various panplacodal genes in Xenopus and the chick (Ahrens and Schlosser 2005; Litsiou et al. 2005). Moreover, grafts of neural plate or dorsolateral endomesoderm are able to induce some panplacodal genes ectopically in nonneural ectoderm of Xenopus and chick embryos (Woda et al. 2003; Glavic et al. 2004; Ahrens and Schlosser 2005; Litsiou et al. 2005). Taken together, these experiments establish neural plate and dorsolateral endomesoderm as important sources of inductive signals for induction of panplacodal genes in the preplacodal region, although the exact role of these tissues appears to differ somewhat among species.
Three classes of secreted proteins have been implicated in the induction of these genes in the preplacodal region: bone morphogenetic proteins (BMPs), FGFs, and Wnts. First, high levels of BMPs have been shown to suppress induction of Six1 in Xenopus, while inhibitors of BMP signaling expand the expression domains of various panplacodal genes in Xenopus and chick embryos without inducing them ectopically (Brugmann et al. 2004; Glavic et al. 2004; Ahrens and Schlosser 2005; Litsiou et al. 2005). Inhibition of BMP signaling (mediated by BMP inhibitors, which reduce effective BMP concentrations by sequestering free BMP protein) is probably a prerequisite for the proper induction of panplacodal genes in the embryo because BMP genes are known to be expressed at relatively high levels in the preplacodal region at early neural-plate stages (Fainsod et al. 1994; Streit et al. 1998). How this is effected is not yet understood but the BMP inhibitor Cerberus is a promising candidate, since it is expressed in the underlying endomesoderm at the appropriate time (Bouwmeester et al. 1996). Some studies have suggested that intermediate levels of BMPs may, in contrast, be required for the induction of panplacodal genes (Brugmann et al. 2004; Glavic et al. 2004), but grafting experiments in Xenopus argue against this gradient model (Ahrens and Schlosser 2005).
The FGFs represent a second class of signals required for induction of panplacodal genes. In Xenopus, FGF8, is required for induction of Six1 and together with BMP inhibitors is sufficient to activate it ectopically in rostral belly ectoderm (Ahrens and Schlosser 2005). In chick, FGFs are able to induce some panplacodal genes (Eya2) directly, whereas others (Six4) are only upregulated by FGF signals followed by BMP and Wnt antagonists (Litsiou et al. 2005). Both the anterior neural plate and the dorsolateral endomesoderm are known to be sources of FGF signals, but the distribution of different FGFs differs among different vertebrates. For example, in Xenopus (but not in chick), FGF8 is strongly expressed in the anterior neural plate and absent from the rostral dorsolateral endomesoderm, making the former the most likely source of FGF signals involved in induction of panplacodal genes (Ahrens and Schlosser 2005).
The third class of signals implicated in induction of panplacodal genes are the Wnts. The canonical Wnt signaling pathway (mediated by the intracellular protein ß-catenin and Lef/Tcf transcription factors) suppresses induction of panplacodal genes in both Xenopus and the chick, while inhibition of canonical Wnt signaling results in the expansion of their expression (Brugmann et al. 2004; Litsiou et al. 2005). At the neural-plate stage, canonical Wnt signals are active in the trunk of the embryo, but are sequestered in the head by Wnt inhibitors secreted from the endomesoderm and neural plate (Litsiou et al. 2005; Bailey and Streit 2006; Schlosser 2006). This suggests that Wnt signals and their inhibitors may be crucially involved in restricting induction of panplacodal genes to the head.
In summary, present evidence suggests that panplacodal genes are induced in ectoderm by a conjunction of BMP inhibitors, FGFs, and Wnt inhibitors emanating from the anterior neural plate and dorsolateral endomesoderm (Fig. 1E). However, not all regions of the embryonic ectoderm are equally responsive to these signals. In Xenopus, ectodermal competence to respond to these signals with panplacodal gene expression is restricted to the nonneural ectoderm (i.e., ectoderm outside of the domains of the neural plate and neural crest) and is absent from neural ectoderm (Ahrens and Schlosser 2005). In contrast, ectodermal competence for induction of the neural crest appears to be confined to neural ectoderm (Ahrens and Schlosser, unpublished observations; Schlosser 2006). The molecular mechanisms underlying these differences in ectodermal competence are still unclear, although transcription factors of the Dlx- and GATA-families, which are confined to the nonneural ectoderm, have been suggested to play a role (reviewed in Schlosser 2006).
The differential distribution of ectodermal competence may be important to precisely position the preplacodal region lateral to the neural plate and neural crest (binary competence model) (Ahrens and Schlosser 2005; Schlosser 2006). An alternative model (neural-plate border-state model) (McLarren et al. 2003; Woda et al. 2003; Brugmann et al. 2004; Glavic et al. 2004; Litsiou et al. 2005) for explaining the precise registration of different ectodermal domains assumes that ectoderm at the neural-plate border is initially induced to form a special border state, which is later subdivided into neural crest and preplacodal domains depending on the concentrations of various signaling molecules such as Wnts. More data are needed to decide between these two models. The "binary competence model" is favored over the "neural-plate border-state model" by the evidence for differential distribution of competence in Xenopus, but whether this also holds true for chick embryos or other vertebrates remains to be determined.
It is still unclear how the various signaling cascades and competence factors cooperate to activate transcription of panplacodal genes. Recently, however, six independent enhancers of Six1 and Six4 genes have been identified in the mouse; these direct expression of these genes in the entire preplacodal region as well as in various subsets of placodes (Sato et al. 2005). Molecular dissection of these cis-regulatory elements promises to reveal which upstream signaling pathways and transcription factors are directly involved in the regulation of Six1 and Six4 transcription in the preplacodal ectoderm and how they are integrated.
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Promotion of placodal development by Six and Eya genes |
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SynopsisIntroductionDevelopment of vertebrate...Induction of Six and...Promotion of placodal...Evolutionary origin of the...References |
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How do the panplacodal Eya genes and Six1/2 and Six4/5 subfamily genes promote placodal development in vertebrates? Insights into the role of these genes have largely come from placodal deficits observed in mutants of Six1 and Eya1 in humans, mice, and zebrafish and recently from knockdown and overexpression of these genes in Xenopus and zebrafish, (Abdelhak et al. 1997
; Xu et al. 1999; Laclef et al. 2003; Zheng et al. 2003; Li et al. 2003; Ozaki et al. 2004; Zou et al. 2004; Brugmann et al. 2004; Ruf et al. 2004; Kozlowski et al. 2005; Friedman et al. 2005; Nica et al. 2006; Bricaud and Collazo 2006; reviewed by Schlosser 2005, 2006); these are briefly summarized subsequently. Six4 mutants are also known from mice, but they do not show dramatic placodal deficits (Ozaki et al. 2001). This may be due to the ability of Six1 to functionally compensate for the loss of Six4 to some degree, as suggested by augmented placodal deficiencies in Six1/Six4 double knockout mice (Grifone et al. 2005; Konishi et al. 2006).
Many placodal derivatives in mutants of Eya1 or Six1 are smaller and often strongly reduced in size. This includes the inner ear and vestibulocochlear ganglion derived from the otic placode, the olfactory epithelium derived from the olfactory placode, lateral-line primordia derived from the lateral-line placode, the profundal and trigeminal ganglia derived from the profundal and trigeminal placodes, and the distal ganglia of the facial, glossopharyngeal, and vagal nerves derived from the epibranchial placodes. The anterior pituitary is relatively normal in single mutants but hypotrophic in Six1/Eya1 double mutants (Li et al. 2003). These decreases are often due to either reduced rates of cell proliferation or increased apoptosis, or both, suggesting that Eya1 and Six1 typically promote proliferation and inhibit apoptosis. Eya1 and Six1 promote proliferation by interaction with cell cycle control genes such as CyclinA1, CyclinD1, and c-Myc (Ford et al. 1998; Li et al. 2003; Coletta et al. 2004; Yu et al. 2006); how they affect apoptosis is unknown.
In addition to reductions in size, Eya1 and Six1 mutants often display abnormal morphogenesis of placodal derivatives. For example, semicircular canals and the cochlear duct in the inner ear do not form properly and fewer neuronal precursors delaminate from the neurogenic placodes. In mutants, morphogenetic movements are also compromised during the development of other tissues in which Eya1 and Six1 are expressed, including the pharyngeal pouches and their derivatives (thymus), kidney, and muscles (Xu et al. 1999, 2002, 2003; Laclef et al. 2003; Grifone et al. 2005; Zou et al. 2006). Interestingly, Six1 has recently been shown to directly transcriptionally activate Ezrin, a protein that links the cytoskeleton to the plasma membrane and may influence cell shape and motility. Moreover, Six1 promotes metastasis of cancer cells in an Ezrin-dependent fashion (Yu et al. 2004, 2006). Taken together, this suggests that Six1 and Eya1 may also be involved in promoting cell shape changes during placode development, for instance during invagination and delamination, but the mechanisms involved remain to be elucidated.
Finally, the differentiation of neurons and sensory cells as well as certain other pathways of cytodifferentiation are compromised in placodal derivatives of Eya1 and Six1 mutants. The reduction in numbers of placodally derived neurons and sensory cells observed in Eya1 and Six1 mutants can be partly attributed to their effects on proliferation and survival discussed earlier. However, there is increasing evidence that Eya1 and Six1 also affect cytodifferentiation more directly. For example, zebrafish, which carry a mutation in Eya1, are deficient in cytodifferentiation of a subset of the neurosecretory cell lineages of the anterior pituitary derived from the adenohypophyseal placode in the absence of apoptosis (Nica et al. 2006). Moreover, neuronal determination and differentiation genes such as Neurogenin1, Neurogenin2, Atonal1, and NeuroD, which are required for the differentiation of neurons and sensory cells from the olfactory, profundal, trigeminal, epibranchial, and otic placodes were shown to be reduced in mutants or after protein knockdown in mice and zebrafish (Xu et al. 1999; Zheng et al. 2003; Zou et al. 2004; Friedman 2005; Ikeda et al. 2006; Bricaud and Collazo 2006). This suggests that Six1 and Eya1 are required for differentiation of placodal neurons and sensory cells. Recent gain and loss of function experiments in Xenopus suggest that Eya1 and Six1 synergistically promote the formation of proliferative neuronal progenitors in neurogenic placodes (characterized by low level Sox3 expression), but must be downregulated to allow terminal neuronal differentiation (Brugmann 2005; Völker, Stammler, and Schlosser). In addition, overexpression and knockdown of Six1 and Eya1 in Xenopus also affects the expression of other transcription factors with more widespread placodal expression (Brugmann et al. 2004).
So far few direct target genes of Six1 and Eya1 have been identified. It is, therefore, still unclear, which of their observed effects on cytodifferentiation are due to their direct interaction with determination genes and differentiation genes (as recently found for the Drosophila neuronal determination gene atonal; Zhang et al. 2006), and which effects rather reflect modulations of the expression of various transcription factors and signaling molecules involved in patterning and regionalization of placodes (Ozaki et al. 2004; Friedman et al. 2005).
The foregoing paragraphs give only a brief overview of the effects of Eya1 and Six1 mutants and necessarily gloss over deviations from the general pattern, so a few caveats need to be made. First, different vertebrate species typically but not always show similar placodal deficiencies after loss of function of Six1 or Eya1. For example, cranial ganglia derived from epibranchial placode are not affected in zebrafish after loss of function in either Eya1 or Six1 (Kozlowski et al. 2005; Bricaud and Collazo 2006), whereas they are strongly reduced or absent in mice mutant for either Eya1 or Six1 (Xu et al. 1999; Zheng et al. 2003; Zou et al. 2004). Second, while Eya1 and Six1 in general are similarly expressed and have similar mutant phenotypes in placodes this is not always the case. For instance, loss of Six1 activity in zebrafish only leads to reductions in cell numbers, but does not affect lineage specification in the anterior pituitary in contrast to Eya1 (Nica et al. 2006). Third, often Six1 and Eya1 affect developmental processes such as proliferation, apoptosis, morphogenesis, or neurogenesis, similarly in different parts of a placode and even in different placodes, but there are exceptions. For example, in zebrafish (but not in mice) Six1 has opposite effects on two cell lineages derived from the otic placode. While it promotes proliferation and inhibits apoptosis in hair cells, it inhibits proliferation and promotes apoptosis in neurons of the vestibulocochlear ganglion (Bricaud and Collazo 2006).
Some of these differences between the function of Eya1 and Six1 in different placodes or species may be due to the existence of multiple paralogues of Six1/2 and Six4/5 subfamily genes and Eya family genes in vertebrates due to genome duplication, and probably even more paralogues in zebrafish due to an additional round of genome duplication in the teleost lineage (Meyer and van de Peer 2005). This allows for the possibility of differential retention of some ancestral functions but not others in different paralogues in different vertebrate lineages (Force et al. 1999). Other differences may relate to placode-specific modifications of the functions of these genes, which may supersede their originally similar role in all placodes. These may involve, for example, the differential expression of cofactors that bind to Six1 or Eya1. Both Six and Eya proteins are known to interact with a number of other proteins that modulate their activity and Six transcription factors can act either as transcription activators or transcriptional repressors, depending on their binding partners (Kobayashi et al. 2001; Zhu et al. 2002; López-Rios et al. 2003; Li et al. 2003, 2004; Silver et al. 2003; Brugmann et al. 2004; Kenyon et al. 2005).
Despite these differences in detail, the balance of available evidence suggests that at least Six1 and Eya1 (and probably other Six1/2, Six4/5, and Eya genes as well) promote similar developmental processes in the different vertebrate placodes and, thus, may control generic placodal properties shared by the different placodes. Their induction in the preplacodal ectoderm may therefore imbue this region with a bias to develop into some kind of placode. Placode-specific pathways of differentiation and morphogenesis may then be controlled by other transcription factors with a more restricted expression (reviewed in Schlosser 2006).
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Evolutionary origin of the new role of Six and Eya genes in the development of vertebrate placodes |
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SynopsisIntroductionDevelopment of vertebrate...Induction of Six and...Promotion of placodal...Evolutionary origin of the...References |
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Six and Eya are ancient metazoan genes. Homologues of the Eya gene have been identified in plants (Takeda et al. 1999
) and homologues of Six genes are present in sponges (Bebenek et al. 2004). The three different subfamilies of Six genes (Six1/2, Six4/5, Six3/6) date back to at least the common ancestor of cnidarians and bilaterians (Kawakami et al. 2000; Stierwald et al. 2004; Bebenek et al. 2004). However, most invertebrates, including protochordates, have only a single Eya gene and one member of each of the three Six subfamily genes indicating that duplications of these genes into four Eya genes and two members for each Six subfamily occurred only in the vertebrate lineage (Xu et al. 1997; Duncan et al. 1997; Borsani et al. 1999; Kawakami et al. 2000; Bebenek et al. 2004; Mazet et al. 2005). What developmental roles did Six1/2, Six4/5, and Eya genes play in ancestral deuterostomes and how did this role change in the ancestors of chordates and vertebrates eventually establishing a central role of these genes in vertebrate placodal development? Because the central role of these genes in vertebrate placodal development requires (1) their proper induction in ectoderm at the neural-plate border and (2) their capacity to drive generic developmental processes of placodes such as proliferation, cell shape changes, and particular pathways of cytodifferentiation (e.g., neurogenesis), we have to ask in particular, when these upstream and downstream regulatory links of Six and Eya genes evolved. Since data on expression and function of these genes have been obtained in only a few taxa, we can at present only attempt to give a tentative answer that may have to be reconsidered as soon as more information becomes available.
However, before considering the changing roles of Six and Eya genes, I should briefly digress to discuss deuterostome phylogeny, since phylogenetic changes in gene function can only be elucidated in reference to an explicit phylogenetic hypothesis. Much of the traditional view of metazoan phylogeny has been revised in the past decade in light of new molecular evidence. Deuterostome relationships, in particular, have been dramatically reinterpreted in the past few years. Due to space limitations, I can only sketch what appears to be the new consensus of deuterostome relationships without discussing the evidence in detail (see in particular, Blair and Hedges 2005; Philippe et al. 2005; Bourlat et al. 2006; Delsuc et al. 2006). Deuterostomes are generally considered a monophyletic group, which is the sister group of the equally monophyletic protostomes. Together, deuterostomes and protostomes comprise the bilateria. Within the deuterostomes, hemichordates and echinoderms are sister groups and together form the Ambulacraria, which probably together with the enigmatic Xenoturbellida comprise the Xenambulacraria. Their sister clade comprises the chordates, which are also a monophyletic group. Within the chordates, the urochordates (comprising ascidians, larvaceans, and thaliaceans) are now—contrary to a long tradition of thought—suggested to be the closest relatives of vertebrates, whereas cephalochordates appear to be the sister taxon of the urochordate/vertebrate clade (Fig. 2B).
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Recruitment of Six and Eya genes to the neural-plate border during deuterostome evolution
When during deuterostome evolution did Six1/2, Six4/5, and Eya genes become recruited to the nonneural ectoderm at the anterior neural plate border? To address this question, the evolutionary origin of the neural plate itself must first be briefly considered. Because the developing central nervous systems (CNS) of Drosophila and vertebrates exhibit multiple similarities in patterns of gene expression and are positioned similarly relative to conserved dorsoventral patterning systems (confinement to regions of low BMP concentrations within a BMP gradient established along the dorsoventral axis) they have been suggested to be homologous structures derived from a common precursor (Arendt and Nübler-Jung 1996
, 1999; Hirth et al. 2003; Lichtneckert and Reichert 2005). In this view, the Urbilaterian ancestor would already have possessed a ventral region of neurogenic ectoderm, which subsequently gave rise to both the ventrally confined neurogenic ectoderm of protostomes and—after dorsoventral axis inversion—to the dorsally confined neurogenic ectoderm of chordates, i.e., the neural plate. This interpretation implies the presence of a—possibly neural plate like—centralized neurogenic domain already in the deuterostome ancestor. However, neither hemichordates nor echinoderms have a neural plate. Instead they develop a relative diffuse nerve net from neuronal precursors scattered throughout the ectoderm. In hemichordates, basically the entire ectoderm is neurogenic (Bullock 1945, Benito and Pardos, 1997; Lowe et al. 2003). The absence of a neural plate in these taxa could of course be due to secondary loss. However, diffuse nerve nets and absence of centralized neurogenic domains in the ectoderm are also found in many protostomian phyla and in cnidarians, making it more likely that this is the ancestral situation for bilaterians, protostomes, and deuterostomes (reviewed in Roth and Wullimann 1996; Holland 2003). According to the latter scenario, centralized neurogenic domains arose several times independently in metazoan evolution and the neural plate specifically originated in chordates (Lowe et al. 2003, 2006; Gerhart 2006).
Regardless of which scenario will turn out to be true, Six1/2, Six4/5, and Eya genes were most likely not specifically localized to nonneural ectoderm adjacent to a CNS precursor domain in the ancestor of deuterostomes. First, they are not specifically localized to the border of the neurogenic ectoderm in Drosophila or other protostomes. Second, expression of the hemichordate Six1/2 gene (expression of Eya or Six4/5 has not been reported) is confined to a small stripe in the anterior mesosome and a prominent domain in the pharyngeal slits, where it is mostly or exclusively endodermal (Gerhart 2006; Lowe, Gerhart, and Kirschner). The latter expression is probably an ancestral feature of deuterostomes, because expression of Six1/2 and/or Eya in the pharyngeal endoderm and in regions where pharyngeal slits form is also observed in urochordates (Bassham and Postlethwait 2005; Mazet et al. 2005;), cephalochordates (Kozmik et al. 2007), and vertebrates (Xu et al. 2002; Zou 2006). Whether Six1/2, Six4/5, and Eya genes were also expressed in parts of the ectoderm of the deuterostome ancestor is currently not clear. The hemichordate data indicate that Six1/2 is absent from most of the ectoderm including the majority of neuronal precursors with possible exception of a small region in the mesosome and around the pharyngeal slits, but the expression of Eya and Six1/2 genes in some neurons in chordates and in many protostomes taken together with recent reports of Eya expression in sea urchin neurons (Burke et al. 2006) suggest that these genes may have been expressed in a subset of scattered ectodermally derived neurons in the deuterostome ancestor (discussed in more detail subsequently).
More is known about the expression of these genes in cephalochordates and urochordates (Fig. 2A). In amphioxus (Kozmik et al. 2007), Six1/2, Six4/5, and Eya are all expressed in the pharyngeal endoderm (including primordia of the pharyngeal slits, mouth, and Hatschek's left diverticulum) and different parts of the mesoderm. Six4/5 and Eya are also expressed in a few domains in the neural plate and CNS (including regions that give rise to ciliary and rhabdomeric photoreceptors). In the nonneural ectoderm only Six1/2 and Eya are expressed in a few scattered cells that may be precursors for a subset of epidermal sensory cells. However, none of these genes is expressed in nonneural ectoderm adjacent to the neural-plate border. In ascidians, Six1/2, Six4/5, and Eya are also expressed in various endodermal and mesodermal domains (Mazet et al. 2005). In contrast to amphioxus, however, both Six1/2 and Eya (but not Six4/5) are also strongly expressed in the nonneural ectoderm adjacent to the anterior neural-plate border. Six1/2 and Eya expression in the anterior nonneural ectoderm appears to be an ancient urochordate feature since it is also observed in larvaceans (although expression at neural-plate stages has not been reported; Bassham and Postlethwait 2005).
Taken together, this suggests that Six1/2 and Eya genes were recruited to the nonneural ectoderm at the anterior neural-plate border in the urochordate/vertebrate lineage after the cephalochordates split off, Six4/5 genes possibly even later. It has been suggested previously, that the new ectodermal expression domain of Six1/2, Six4/5, and Eya genes may have evolved by expansion and acquisition of independent regulation from an ancestral expression domain in the pharyngeal endoderm (Schlosser 2005). Alternatively, cells expressing Six1/2 and Eya (and possibly Six4/5) that were originally scattered throughout the ectoderm may have become concentrated in anterior nonneural ectoderm by becoming dependent on a combination of inducers confined to that region. Unfortunately, we cannot presently decide between these scenarios because nothing is known about upstream inducers and regulators of Six and Eya gene expression in amphioxus or ascidians.
Acquisition of new functions by Six and Eya genes during deuterostome evolution
After considering the evolutionary origin of a new expression domain of Six1/2, Six4/5, and Eya genes adjacent to the anterior neural-plate border in deuterostomes, we now have to turn to the second question. When during deuterostome evolution did these genes acquire their capacity to regulate developmental processes typical for vertebrate placodes, for example, proliferation, cell shape changes, and particular pathways of cytodifferentiation (e.g., neurogenesis)? This question is more difficult to address and the answer will depend on whether the situation in extant hemichordates resembles the ancestral deuterostomian condition or is secondarily simplified. As already mentioned, in hemichordates scattered neurons originate from the entire ectoderm, in which Six1/2 is not expressed. So if extant hemichordates retain the ancestral deuterostome condition, Six1/2—and possibly Six4/5 and Eya genes as well—initially played no prominent role in the regulation of neurogenesis in the deuterostome ancestor. Instead, it may have functioned in regulating various aspects of the formation of pharyngeal gill slits and, judged from the conserved expression of these genes in the pharyngeal endoderm in chordates, this function was probably retained in chordates. Indeed in mammalian mutants of Six1 and Eya1, the patterning and morphogenesis of pharyngeal pouches is abnormal, apoptosis is increased, and several pharyngeal pouch derivatives (e.g., thymus) do not develop properly (Xu et al. 2002; Laclef et al. 2003; Ozaki et al. 2004; Zou et al. 2006).
Interestingly, Six and Eya genes have also been shown to regulate apoptosis and morphogenetic movements in the developing compound eye of Drosophila and their expression is associated with a variety of regions, where cell shape changes take place in a number of protostomes and deuterostomes (Cheyette et al. 1994; Serikaku and O'Tousa 1994; Bonini et al. 1993, 1998; Pignoni et al. 1997; Seo et al. 1999; Arendt et al. 2002; Stierwald et al. 2004; Mazet et al. 2005; Bassham and Postlethwait 2005; Kozmik et al. 2007). This suggests that the promotion of cell shape changes may be among the evolutionarily most ancient functions of these genes, although nothing is at present known about the mechanisms involved.
Whereas there is currently no evidence for a role of Eya or Six1/2 in neurogenesis in hemichordates, expression patterns are compatible with a role for the development of some neurons and neurosecretory cells in protochordates (Fig. 2A). In contrast to hemichordates, Eya, and Six1/2 genes are expressed in a few scattered ectodermal cells in amphioxus, which have been hypothesized to be precursors for a subset of epidermal sensory cells and may be either chemoreceptors or mechanoreceptors (Kozmik et al. 2007). However, many other sensory cells and neurons in amphioxus (reviewed in Holland and Holland 2001; Lacalli 2004; Holland 2005; Schlosser 2005) arise from regions of the general ectoderm devoid of Eya, Six1/2, and Six4/5 expression. The secretory cells of Hatschek's pit, which are immunopositive for some of the gonadotropins and neuropeptides found in the vertebrate adenohypophysis (reviewed in Schlosser 2005), also appear to originate from tissue expressing Eya and Six1/2 in amphioxus, viz. Hatschek's left diverticulum, which is, however, an endodermal stucture (Kozmik et al. 2007).
In contrast, in urochordates all neurosecretory cells immunopositive for adenohypophyseal hormones arise from the anterior neural plate and not from the Six1/2 and Eya expressing ectoderm adjacent to it (reviewed in Schlosser 2005), suggesting that urochordates may have lost a Hatschek's-pit-like rostral neurosecretory organ. However, various kinds of sensory cells (reviewed in Bone and Mackie 1982; Holland 2005; Mackie and Burighel 2005; Schlosser 2005) probably originate from regions of Six1/2 and Eya expression. The mechanoreceptive cells of the coronal organ of ascidians and similar cells of the circumoral organ of larvaceans (secondary sensory cells without an axon) originate from the domain of Six1/2 and Eya gene expression in the anterior nonneural ectoderm as do the chemosensory neurons of the larvacean ventral organ (primary sensory cells with an axon) (Bassham and Postlethwait 2005; Mazet et al. 2005). In addition, the Langerhans cells of larvaceans, a specialized type of secondary mechanosensory cells express Eya but not Six1/2 (Bassham and Postlethwait 2005). In ascidians, Eya, Six1/2, and Six4/5 are also expressed in ectoderm of the atrial primordia, from which a number of mechanoreceptive sense organs composed of primary sensory cells arise, such as the cupular and capsular organs (Mazet et al. 2005). Furthermore, Eya but none of the Six genes, is expressed in ectoderm giving rise to the palps with primary mechano- and chemo-sensory cells. However, other sensory cells, such as the mechanoreceptive primary sensory neurons in the ascidian tail probably originate from regions of the general ectoderm devoid of Eya, Six1/2, and Six4/5 expression (Mazet et al. 2005). Although direct experimental evidence is still lacking, these expression patterns indicate that Eya and Six genes may have acquired a new role in controlling development of some neurons and neurosecretory cells in the chordate lineage (Fig. 2B) before they adopted a more central role in placodal neurogenesis in vertebrates (as discussed subsequently).
The scenario presented so far rests on the assumption that extant hemichordates, in which there is presently no evidence for a role of Six1/2 in neurogenesis, retain the ancestral deuterostome condition. However, we also need to consider the alternative possibility that Six1/2, Six4/5, and Eya were already employed in the control of neuronal development in the deuterostome ancestor and that this function was secondarily lost in hemichordates. There is in fact some evidence supporting the latter possibility. First, there is some indication that at least Eya is expressed in neurons of sea urchins, although this needs to be confirmed by expression studies (Burke et al. 2006). Second, Six1/2, Six4/5, and/or Eya genes are expressed in regions, where neurogenesis takes place in a number of different protostomes (insects, nematodes, planarians, and polychaetes) as well as in cnidarians (Bonini et al. 1993, 1997; Cheyette et al. 1994; Serikaku and O'Tousa 1994; Seo et al. 1999; Arendt et al. 2002; Stierwald et al. 2004). Third, functional studies in Drosophila and planarians directly demonstrate functions of Six1/2 and Eya genes for neuronal development in the eyes (e.g., Cheyette et al. 1994; Serikaku and O'Tousa 1994; Bonini et al. 1993, 1997; Pignoni et al. 1997; Halder et al. 1998; Suzuki and Saigo 2000; Pineda et al. 2000; Mannini et al. 2004).
Recently, the Six1/2 homologue sine oculis in conjunction with the Pax6 homologue eyeless has been shown to directly regulate expression of the neuronal determination gene atonal, which initiates a cascade of events leading to differentiation of photoreceptors in the Drosophila eye (Zhang et al. 2006). Since Six1/2 homologues are also coexpressed with PaxB-like genes (Pax6-Pax2/5/8 related genes) and atonal-related genes in cnidarians, polychaetes, and vertebrates (reviewed in Piatigorsky and Kozmik 2004; Fritzsch and Piatigorsky 2005; Tessmar-Raible et al. 2005) in regions where various sense organs including photoreceptors and mechanoreceptors develop, it has been suggested that Six1/2 genes together with PaxB-like genes may have controlled an ancient bilaterian protosensory organ with atonal-dependent neurogenesis, which gave rise to atonal-dependent sensory organs in protostomes and deuterostomes (Zhang et al. 2006). Less is known about Eya and Six4/5 genes, but there is evidence for coexpression and/or functional interaction of Six1/2 and Eya in insects, nematodes, and planarians suggesting that cooperation of these genes in at least some of their expression domains are also shared among bilaterians (Pignoni et al. 1997; Li et al. 2004; Mannini et al. 2004).
These findings are, however, not sufficient to establish whether Six1/2 indeed plays homologous roles in these various neuronal cell types or whether different neuronal cell types acquired Six1/2-dependent regulation independently. The latter possibility must be seriously considered, because there appears to be neither an evolutionarily conserved association of Six1/2 genes with atonal-dependent neurogenesis nor with particular modalities of sensory cells as briefly summarized in the following paragraphs.
For example, whereas atonal-dependent precursors for photoreceptors in Drosophila express Six1/2, atonal-dependent precursors for the mechanoreceptive chordotonal organs and Johnston's organs do not (Jarman et al. 1993; Cheyette et al. 1994; Serikaku and O'Tousa 1994). Similarly, Six1/2 is coexpressed with atonal in the precursors of larval and adult photoreceptors in polychaetes, but absent from the atonal-expressing neuronal precursors of the apical organ (Arendt et al. 2002). In ascidians, atonal may be coexpressed with Six1/2 in anterior ectoderm, from which the mechanosensory coronal organ develops, whereas only atonal, but not Six1/2, is expressed in the presumptive mechanosensory cells of the tail (Mazet et al. 2005; http://ghost.zool.kyoto-u.ac.jp/tfst.html). Moreover, there are other classes of neurons, which require genes related to Drosophila achaete–scute rather than atonal-related genes for initiation of neuronal differentiation (reviewed in Hassan and Bellen 2000). In vertebrates, for example, specification of olfactory receptor neurons that arise from the Six- and Eya-expressing preplacodal ectoderm require the achaete–scute homolog Ash1 (Cau et al. 1997, 2002; Murray et al. 2003). Expression patterns also suggest the possibility that Six1/2 colocalizes with both atonal-dependent and achaete–scute-dependent neuronal precursors in cnidarians (Müller et al. 2003; Seipel et al. 2004; Stierwald et al. 2004), but this requires further study.
Although more data are needed to obtain a clear picture, these findings argue against an evolutionarily conserved connection between Six1/2 and atonal-dependent neuronal differentiation and rather suggests that Six1/2 (and possibly Six4/5 and Eya as well) may have repeatedly gained or lost a regulatory role in the context of various gene circuits governing neuronal differentiation. Interestingly, atonal-related and achaete–scute-related genes are already differentially expressed in cnidarians and each of these genes is known to be important for specification of sensory cells of different modalities in various lineages suggesting that sensory modalities of sensory cells may be evolutionarily quite flexible (reviewed by Tessmar-Raible et al. 2005; Schlosser 2005). Six1/2 expression does not appear to be linked to any particular sensory modality either: it is expressed in prospective photoreceptors in polychaetes and insects, but not in cnidarians and vertebrates and is expressed in prospective mechanoreceptors or chemoreceptors in chordates, and possibly in cnidarians but not in insects (Arendt et al. 2002; Cheyette et al. 1994; Serikaku and O'Tousa 1994; Stierwald et al. 2004).
In conclusion, current evidence is insufficient to decide whether Six1/2, Six4/5, or Eya genes were already employed in the control of some aspects of neuronal development in the deuterostome ancestor (with secondary loss in hemichordates) or whether a more ancient role of these genes in neuronal control was lost in the deuterostome ancestor and reacquired in the chordate lineage (Fig. 2B). Moreover, it is questionable which, if any, of the Six1/2 and Eya expressing sensory cells in protochordates are homologous to placodally derived sensory cells or neurons in vertebrates (reviewed in Holland 2005; Schlosser 2005). Be that as it may, the expression of Six1/2 and Eya genes in only a subset of scattered ectodermal sensory neurons in amphioxus and ascidians, and some neurosecretory cells in amphioxus is certainly in striking contrast to the situation observed in vertebrates. First of all, in vertebrates no sensory neurons arise from nonneural ectoderm outside the preplacodal region defined by Six1/2 and Eya expression. Second, the Six1/2 and Eya expressing preplacodal region in vertebrates gives rise to dense clusters of sensory neurons rather than to merely scattered cells. Many additional cell types without precursors in the nonneural ectoderm of amphioxus and ascidians (e.g., lens cells and many neurosecretory cell types of the olfactory and adenohypophyseal placodes) also arise from the preplacodal region in vertebrates, but it remains to be shown, which of these develop in a Six- and Eya-dependent fashion. This strongly suggests that Six and Eya genes have adopted additional and more central roles in regulation of neuronal differentiation and possibly other pathways of cytodifferentiation as well specifically in the vertebrate lineage and hence after recruitment of these genes to the nonneural ectoderm at the anterior neural-plate border (Fig. 2B). The absence of neurons from ectoderm devoid of Six and Eya expression in vertebrates suggests that Six/Eya-independent types of sensory neurons were either lost in the vertebrate lineage or did secondarily acquire Six/Eya-dependent regulation. The dramatic increase in neuronal density in Six and Eya expressing ectoderm in vertebrates, on the other hand, may be due to either a novel role of Six and Eya genes in regulating the proliferation of neuronal precursors or a reduced requirement for cofactors in the regulation of neuronal determination genes. Only additional functional studies analyzing how Six and Eya genes regulate cytodifferentiation in vertebrate placodes and in protochordate sensory cells will allow us to resolve these questions and to further elucidate how these old genes adopted new functions during the evolution of vertebrate cranial placodes.
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From the symposium "Linking Genes and Morphology in Vertebrates" presented at the annual meeting of the Society for Integrative and Comparative Biology, January 3–7, 2007, at Phoenix, Arizona.
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