Reelin, Cajal–Retzius Cells, and Cortical Evolution

1.06 Reelin, Cajal–Retzius Cells, and Cortical Evolution F Tissir and A M Goffinet, University of Louvain Medical School, Brussels, Belgium ª 2007 Elsevier Inc. All rights reserved.

1.06.1 1.06.2 1.06.3 1.06.4 1.06.5

Introduction Reelin Signaling During Cortical Development and Evolution The Puzzle of Cajal–Retzius Cells Redundant Expression of Reelin in Mice: What Could It Teach Us about Evolution? Conclusions

Glossary CP Dab1 DC DVR LC MC Myr MZ VZ

Cortical plate. Disabled-1 gene or protein. Dorsal cortex. Dorsal ventricular ridge. Lateral cortex. Medial cortex. Mega-year. Marginal zone. Ventricular zone.

1.06.1 Introduction One of the most fascinating questions in neurobiology concerns the evolution of the cerebral cortex, a sequence of events that leads to the development of the human cortex and its cognitive abilities (see The Development and Evolutionary Expansion of the Cerebral Cortex in Primates). Genes that control development and growth are privileged targets of evolutionary selection (Raff, 1996), and comparative studies of cortical development may shed light on this process (see Cortical Evolution as the Expression of a Program for Disproportionate Growth and the Proliferation of Areas; Captured in the Net of Space and Time: Understanding Cortical Field Evolution). In the absence of fossil material, however, the evolution of cortical development can only be inferred from comparative studies of modern organisms (Butler and Hodos, 1996). Studies carried out during the last decades demonstrated that basic, conserved developmental mechanisms pattern the brain in general and the telencephalon in particular (Monuki and Walsh, 2001; Grove and Fukuchi-Shimogori, 2003). Secreted factors (such as Shh, Wnts, Bmps, and Fgfs) establish morphogenetic gradients to which precursors in the neuroepithelial sheet respond by modulating expression of arrays of transcription

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factors (such as Pax6, Emx1/2, and Tbr1), thereby adapting neuronal cell numbers and types. Different neuronal classes migrate following different routes to colonize various structures. The cortex is reduced to a periventricular layer in anamniotic vertebrates and increases in size and organization in amniotes. It gains prominence in synapsids, the lineage leading to mammals, and evolves explosively in primates. Despite their obvious importance, however, the molecular events that underlie cortical evolution remain mostly unknown. Work in mice identified several genes with a role in cortical development and presumably evolution (Lambert de Rouvroit and Goffinet, 2001; Monuki and Walsh, 2001). Among them, reelin and its signaling partners may be critical players in the evolution of the mammalian laminar cortical plate (CP) (Bar et al., 2000). In addition, in humans, reelin signaling is essential for cortical foliation (Hong et al., 2000). Comparisons of reelin expression in mammals, reptiles, and birds show that reelin-expressing cells are present in the cortical marginal zone (MZ), from the preplate (PP) stage, in all amniotes, but both the number of positive cells and their level of expression are much higher in mammals than in other lineages. In this article, we will briefly review data on comparative reelin expression during cortical development and discuss some questions that we consider of special neurobiological interest because they would be amenable to study, provided more efforts are invested to provide access to genomic sequences and high-quality embryonic material from multiple species.

1.06.2 Reelin Signaling During Cortical Development and Evolution A schematic cladogram of evolutionary filiations from stem amniotes to modern reptiles, birds, and mammals is provided in Figure 1 (Colbert et al., 2001). In all

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Reelin, Cajal–Retzius Cells, and Cortical Evolution

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Stem amniotes (320–340)

Swazian Isuan Hadean

Figure 1 Summary of geological epochs, and simplified evolutionary filiations of amniotes. Numbers refer to estimated time of phyletic divergence (in mega-years (Myrs)). Adapted from Bar, I., Lambert de Rouvroit, C., and Goffinet, A. M. 2000. The evolution of cortical development. An hypothesis based on the role of the reelin signaling pathway. Trends Neurosci. 23, 633–638, with permission from Elsevier.

amniotes, telencephalic development follows a basic, evolutionary homologous Bauplan. This basic organization includes a medial, dorsal, and lateral cortex located at the external aspect of the ventricle, and the dorsal ventricular ridge (DVR) located ventral to the ventricle (Figure 2). There is a consensus that the medial cortex is homologous to the mammalian hippocampal formation, whereas the dorsal and lateral cortices are the precursors of the neocortex and the pyriform cortex or rhinencephalon, respectively. Views about the DVR, which is diminutive in mammals, are more controversial (Northcutt, 1981; Butler and Hodos, 1996; Fernandez et al., 1998). In mammals, cortical development begins with the appearance of the PP (Caviness, 1982; Allendoerfer and Shatz, 1994; Sheppard and Pearlman, 1997; Super et al., 2000), a heterogeneous structure that contains future subplate cells, reelin-negative pioneer neurons and reelin-positive subpial cells destined for the MZ (Meyer et al., 1998, 2000), and probably other cell types. The next stage is the condensation of the CP,

densely populated with radial bipolar neurons. The appearance of the CP results in the splitting of the PP, elements of which are displaced in the subplate (Allendoerfer and Shatz, 1994) and in the MZ (Caviness, 1982; Sheppard and Pearlman, 1997). The CP develops from inside to outside, by migration of new neurons that cross previously established layers and settle at progressively more superficial levels. The organization of the CP is controlled by the reelin-signaling pathway (Rice and Curran, 2001; Tissir and Goffinet, 2003). Defective reelin signaling results in a loosely organized CP, with absence of PP splitting, and inverted maturation, from outside to inside (Caviness and Rakic, 1978; Rakic and Caviness, 1995). Normal reelin signaling is necessary but not sufficient for the development of the CP. For example, in mice deficient in cyclin-dependent kinase 5 (Cdk5) or its cofactors p35 and p39 (Ohshima et al., 1996; Chae et al., 1997; Gilmore et al., 1998; Ko et al., 2001), the radial organization of the early CP is preserved, yet its maturation proceeds from outside to inside as in

Reelin, Cajal–Retzius Cells, and Cortical Evolution 91

Figure 2 Schematic organization (frontal sections) of the dorsal embryonic telencephalon in putative stem amniotes, chelonians (turtles), squamates (lizards and snakes), archosaurs (birds and crocodiles), and mammals. BF, basal forebrain; DC, dorsal cortex (mammalian NC, neocortex); DVR, dorsal ventricular ridge; LC, lateral cortex (mammalian Rh, rhinencephalon); MC, medial cortex (mammalian Hip, hippocampus); MGE and LGE, medial and lateral ganglionic eminences; Sep, septal nuclei; Str, striatum; Wu, avian Wulst. Reproduced from Bar, I., Lambert de Rouvroit, C., and Goffinet, A. M. 2000. The evolution of cortical development. An hypothesis based on the role of the reelin signaling pathway. Trends Neurosci. 23, 633–638, with permission from Elsevier.

reelin-deficient mice. Two reelin-dependent developmental events, CP organization and inside-out maturation, were presumably also important acquisitions during cortical evolution (Bar et al., 2000). Additional factors of cortical evolution include increased neuron generation in the ventricular zone (VZ) and the necessity to migrate over longer distances, requiring a sophisticated migration machinery in which Cdk5, p35/p39, and other genes such as filamin-1, Lis1, or doublecortin participate (Lambert de Rouvroit and Goffinet, 2001; Grove and Fukuchi-Shimogoril, 2003). Reelin is a large extracellular glycoprotein that is secreted by Cajal–Retzius neurons in the MZ (Bar et al., 1995; D’Arcangelo et al., 1995). It binds to two receptors of the lipoprotein receptor family, very low density lipoprotein receptor (VLDR) and apolipoprotein E receptor type 2 (ApoER2) that are expressed at the surface of CP cells (Hiesberger et al., 1999; Trommsdorff et al., 1999). This triggers the activation of an intracellular signal that ultimately directs the architectonic organization of the CP. Upon reelin-receptor binding, the adapter disabled-1 gene or protein (Dab1) is tyrosine phosphorylated by

Scr family kinases (Howell et al., 2000), but the rest of the mechanism is still poorly understood (Bock et al., 2003; Pramatarova et al., 2003; Ballif et al., 2004; Jossin et al., 2004). Reelin and Dab1 expression have been studied in mouse (Rice and Curran, 2001; Tissir and Goffinet, 2003), human (Meyer and Goffinet, 1998; Meyer et al., 2002, 2003), turtle (Bernier et al., 1999), lizard (Goffinet et al., 1999), chick (Bernier et al., 2000), and crocodile (Tissir et al., 2003), allowing comparisons and correlations with architectonic patterns in representatives of the main amniote lineages (Figure 3; Goffinet, 1983). The expression of VLDLR and ApoER2 is supposed to overlap largely that of Dab1, but this remains to be studied. In turtles, which are considered the most closely related to stem amniotes, cortical architectonics is the most rudimentary. Reelin-positive neurons are present in the MZ of the medial and dorsal cortical fields. In addition, some less strongly labeled neurons are dispersed in the CP. The situation in the lateral cortex is different, with reelin-positive neurons scattered diffusely in the cortex (Bernier et al., 1999). Dab1 is expressed in CP cells in all sectors

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(a)

(a′)

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Figure 3 Comparison of reelin mRNA expression. Frontal sections in the embryonic cortex of the mouse (a, a9), turtle (b, b9), lizard (c, c9) and chick (d, d9). Expression patterns of reelin mRNA are shown in darkfield views (a–d). Schematic drawings (a9–d9) show reelin-positive zones (circles for cells in marginal zone, and hatched areas for more diffuse expression in cortical plate or subcortex). CP, cortical plate; DC, dorsal cortex; DVR, dorsal ventricular ridge; LC, lateral cortex; MC, medial cortex; V, ventricle. a, a9, The mouse cortex is characterized by an almost continuous subpial layer of neurons that express extremely high levels of reelin. The underlying CP is reelin-negative but expresses Dab1. Detailed descriptions are provided in Alcantara et al. (1998) and Schiffmann et al. (1997). b, b9, In the turtle cortex, reelin-positive cells (arrows) are dispersed in the marginal zones of the MC and DC, and to a lesser extent in the lateral cortex and DVR. The cortical plate in MC and DC is weakly reelin-positive and Dab1-positive. Arrowheads point to spontaneously darkfield-positive melanophores. Detailed description in Bernier et al. (1999). c, c9, In the lizard MC and DC, reelin-positive neurons (arrows) are abundant in the marginal zone, and there is a second layer of reelin expression in the subplate (hatched area in c9), whereas the cortical plate is reelin-negative but Dab1-positive. The LC is diffusely Dab1-positive, and its dorsal component expresses reelin (hatched in c9). Detailed description in Goffinet et al. (1999). d, d9, In the chick, subpial reelin-positive cells (arrows) are found only in the diminutive MC (hippocampus) and DC (parahippocampus), and the cortical plate is negative. There is diffuse reelin expression in the LC. Detailed description in Bernier et al. (2000).

(Goffinet, unpublished). In chicks (Bernier et al., 2000), a CP is evident only in the medial cortex and in the adjacent, dorsal parahippocampal cortex. At this level, a few strongly reelin-positive neurons are found in the MZ, but not in the CP itself. A similar canvas of reelin-positive cells in the MZ and reelin-negative CP is found in crocodiles (Tissir et al., 2003). Dab1 expression has not been studied in the chick and crocodilian telencephalon.

In lizards (squamates), an elaborate architectonic organization of the medial and dorsal cortices develops in parallel with a specific, bilaminar expression of reelin, bracketing a reelin-negative and Dab1positive CP (Goffinet et al., 1999). Large reelinpositive neurons are present in the MZ, as in other species. Unlike in other amniotes, a second layer of reelin-positive cells is found in the subcortex. As in turtles, the lateral cortex expresses both reelin and

Reelin, Cajal–Retzius Cells, and Cortical Evolution 93

Dab1. In turtles, lizards, and chicks, maturation of the CP proceeds from outside to inside (as in reelindeficient mammals; Tsai et al., 1981; Goffinet et al., 1986). Mammals (synapsids) are characterized by a spectacular development of the CP both in terms of cell numbers and architectonic organization, and by its maturation from inside to outside (Caviness and Rakic, 1978; Rakic and Caviness, 1995). This is accompanied by an amplification of reelin production in Cajal–Retzius cells (CRc) – as estimated using in situ hybridization with species-specific probes and monoclonal antibodies with conserved epitopes – and anomalies in reelin-deficient mice indicate that this modification of reelin expression was necessary for the evolution of the mammalian cortex. Although several pieces of the puzzle are lacking, such as the expression of lipoprotein receptors and the analysis of more species, these data clearly suggest that the production of reelin by early neurons in the MZ and the expression of Dab1 (and reelin receptors) by CP neurons is a feature of all amniotes. This pattern, presumably present in stem amniotes, is evolutionarily homologous. From this ancestral pattern, the expression profiles have evolved differently in divergent lineages; similar elaborate CP organizations in mammals and in some cortical areas in lizards were probably acquired by convergent evolution. In addition to the control of neuronal numbers and differentiation, and of hodological relationships, the modulation of architectonic organization is an important, hitherto neglected, parameter of cortical evolution, in which the reelinsignaling pathway plays an important role.

1.06.3 The Puzzle of Cajal–Retzius Cells CRc are complex neuronal cells that develop early in the mammalian cortical MZ and undergo apoptotic degeneration near the end of cortical neuronal migration (Del Rio et al., 1996; Mienville, 1999; Frotscher et al., 2001; Grove and Fukuchi-Shimogori, 2003). They have multiple origins in telencephalic VZs and migrate in the PP by following several routes, particularly by tangential migration (Meyer and Wahle, 1999; Meyer et al., 2002; Takiguchi-Hayashi et al., 2004). In spite of heterogeneity of origin and migration pathways, mammalian CRc are uniquely characterized by a co-expression of reelin and the transcription factor p73, a member of the p53 family (Kaghad et al., 1997; Yang et al., 2000; Meyer et al., 2002) that may regulate their apoptosis. As mentioned above, reelin-positive neurons are present in the early MZ in all amniotes, indicating, as a parsimonious hypothesis, that these cells may all be evolutionary-related and could have evolved

from an ancestral CRc present in stem amniotes. On the other hand, the neuronal population of the embryonic MZ is more complex than previously thought (Meyer et al., 1998; Fairen et al., 2002), suggesting that the evolutionary history of CRc may be more intricate than such a simple evolutionary homology. Recently, co-expression of reelin and p73 was shown to be a defining feature of embryonic CRc in humans and rodents (Yang et al., 2000; Meyer et al., 2002). In order to assess whether CRc are indeed evolutionarily homologous, we studied reelin and p73 mRNA expression using double in situ hybridization with species-specific probes in the embryonic cortex of mice, turtles, lizards, crocodilians, and chicks. As illustrated in Figure 4, early-born neurons in the embryonic cortical MZ in turtles and crocodiles co-express reelin and p73, as they do in mammals. The two probes label the same cells and single positive cells are rare. In turtles, the reelin-positive cells scattered in the CP are p73-negative. In crocodiles, the stream of reelin mRNA-expressing cells in the intermediate zone (Tissir et al., 2003) does not express p73 and thereby differs from MZ cells. Rather surprisingly, in chicks, despite the close similarity in terms of brain organization and evolutionary relationships with crocodiles, reelin and p73 are rarely co-expressed in MZ neurons. Similarly, in lizards, very few among the abundant reelin-positive MZ neurons are labeled with the p73 probes. There are several possible explanations to these findings, such as trivial problems in cloning and using p73 mRNA probes. p73 mRNA sequences are closely related to p53 and even more so to p63, and proved particularly difficult to clone in lizards. But, even with that restriction, the results at least show that expression of p73 is very low in chick and lizard and/or that reelin and p73 co-expression is rare in those species. The p73 gene is thought to regulate apoptosis and this regulation may be less important in reelin-positive subpial cells in chicks and lizards than in other species. If this is true, the co-expression of p73 and reelin may not be the best criterion to assess putative evolutionary homologies. Reelin-positive neurons are present in the developing brain of the lamprey (PerezCostas et al., 2002), zebra fish, and Xenopus (Costagli et al., 2002), and the p73 gene was identified in zebra fish (Pan et al., 2003; Rentzsch et al., 2003). With the discovery of new molecular markers and the definition of more genomic sequences, tools should become available in the coming years to unravel the complex evolutionary history of MZ neurons.

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p73 Overlay

Figure 4 Co-localization of reelin and p73 mRNA in CRc. Double in situ hybridization studies of reelin mRNA (digoxigenin-labeled probes, first row), p73 mRNA ([33P]-labeled probes, second row), and their co-localization (overlay, third row) in the embryonic cerebral cortex of the mouse (a–c), turtle (d–f), and crocodile (g–i). Almost all subpial reelin-positive neurons express p73 in all three species. In contrast, the reelin-positive cells in the turtle cortical plate (d, arrowheads) and in the crocodilian subcortex (g, arrow) are p73-negative. Note that the reelin signal illustrated in the mouse was underexposed for histological analysis and is relatively much higher than in other species. PIA, pial surface; MZ, marginal zone; V, lateral ventricle; VZ, ventricular zone. Scale bar: 100mm (a, d, g); 50mm (c, d, f).

1.06.4 Redundant Expression of Reelin in Mice: What Could It Teach Us about Evolution? The reelin expression studies summarized above clearly demonstrate a drastic amplification of the mRNA and protein levels in mammalian CRc as compared to other reelin-positive neurons in the reptilian and avian MZ. It is tempting to assume that high levels of reelin are required during cortical spreading, and indeed a sustained supply of reelinpositive cells is observed in the human MZ throughout fetal development (Meyer and Goffinet, 1998). On the other hand, there is ample evidence that the concentration of reelin in the mouse cortical MZ is in large excess. The reeler (reelin-deficient) mutant phenotype only appears in brains of chimeric mice when reeler cells greatly outnumber normal cells (Mikoshiba et al., 1986; Terashima et al., 1986; Mullen et al., 1997; Yoshiki and Kusakabe, 1998). In spite of a loss of CRc and a drastic decrease of reelin concentration, homozygous p73 mutant mice do not have a reeler-like cortex (Yang et al., 2000). A normal CP develops in vitro in serum-free culture medium without the addition of exogenous reelin, and addition of reelin to reeler slice in vitro (Jossin

et al., 2004), or ectopic expression of low levels of reelin in the VZ in transgenic reeler mice malformation (Magdaleno et al., 2002), are able to partially correct the reeler trait. These observations suggest that reelin may diffuse from sources other than CRc and that the expression of receptors and Dab1 may be more important than the site of ligand production. Why did mammalian CRc amplify a production that appears so redundant in mice? As a way of explaining this apparent contradiction, we would like to suggest the following scenario. Amplification of reelin synthesis in CRc was necessary for the development of a foliated cortex, and stem mammals initially developed a moderately folded, not a lissencephalic, cortex. During evolution, some cortices, such as that of rodents, evolved secondarily into a lissencephalic type. Not being detrimental, elevated reelin production in CRc was not necessarily adjusted in parallel with the reduction of cortical surface. Other lineages, most notably primates, acquired increasingly more foliated cortex and, in humans, additional numbers of reelin-expressing cells became necessary. This idea is compatible with observations that cortical foliation can vary widely within closely related

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lineages. For example, in monotremes, Echidna has an elaborate, highly foliated cortex, whereas Platypus is almost lissencephalic (Rowe, 1990). Similar examples can be found in other phyla, including primates. Production of a gyrated mouse cortex is artificially accomplished by elegant, yet relatively simple, manipulations (Rakic, 2004), such as germline inactivation of caspases 3 and 9 (Kuida et al., 1996, 1998), increased expression of beta-catenin in transgenic mice (Chenn and Walsh, 2002, 2003), or incubation of embryonic cortex in vitro in the presence of lysophosphatidic acid (Kingsbury et al., 2003; Price, 2004). When such an increase in foliated cortex is observed, the cortical ribbon is nearly normal and, unlike the reeler cortex, shows that the production of reelin is largely sufficient. These observations indicate that the production of a gyrated cortex does not require extensive genetic modifications and could have evolved in any phylum, for example, by acquisition of more precursors of radial units in VZs. As no living species are closely related to stem mammals, the hypothesis proposed above will always remain somewhat speculative. However, it predicts that, in a given lineage, the density of reelin-positive cells (per cortical surface area) should be higher in the embryonic brain of representatives with a smooth cortex than in those with a gyrated cortex. The mean density of reelin-positive cells, averaged over large areas, including gyral crowns and sulci, could be compared in embryonic cortices of rodents versus animals that are thought to have evolved little, but have some cortical gyration, such as hedgehogs or spiny anteaters. Potentially the best possible test would be to compare the density of CRc in the embryonic MZ of Echidna and Platypus. All components of the reelin and other signaling cascades were probably present in stem amniotes, available as basic building blocks for cortical evolution. Why then did significant cortical foliation occur only in mammals? Foliation correlates nicely with cortical volume and may be required to increase it beyond some threshold, but how is it achieved? Surely the amplification of reelin production in MZ cells was not the sole limiting factor, as the examples above indicate, nor was the necessary increase in the number of radial cortical units. We would propose that increased reelin synthesis and the development of an enlarged number of precursors and radial cortical units were not hard to achieve, but that the resulting increase in cortical surface did not occur widely because it was difficult to master for some unknown reason. One difficulty could be

the coordinate growth of mesodermal components, such as blood vessels and the cranial envelope that must accompany brain growth. Another problem that had to be solved in order to evolve a laminarly organized and tangentially widespread cortex is that of increased neuronal excitability and susceptibility to seizures. A consequence of the highly geometrical arrangement of radial cortical columns is that it facilitates modification of the membrane potential by field effects (ephaptic interactions), largely believed to be involved in the oscillations of electrocortical rhythms such as the alpha or theta rhythms. This quasicrystalline arrangement presumably has advantages in terms of computational power, but also comes at a price, as ephaptic excitation facilitates the tangential spreading of activity and decreases the threshold for aberrant epileptic discharges (McCormick and Contreras, 2001).

1.06.5 Conclusions Despite the huge complexity of the question, our understanding of cortical evolution has progressed recently in parallel with our understanding of developmental mechanisms. Further advances can be made by careful comparative analyses of cortical development in different species, using simple techniques such as comparative genomics, immunohistochemistry, and in situ hybridization. Two conditions are requisite to make this possible, however. First, genomic sequences should be available for monotremes and at least one member of other amniote lineages (chelonians, crocodilians, sphenodon, squamates). Second, a significant multi-national effort should aim at providing access to high-quality embryonic material from representatives of these lineages.

Acknowledgments This work was supported by grant 2.4504.01 from the Fonds de la Recherche Scientifique et Me´dicale, grants 186 and 248 from the Actions de Recherches Concerte´es, by the Fondation Me´dicale Reine Elisabeth, all from Belgium, and by grant QLGT2000-CT-00158 from the European Union.

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Reelin, Cajal–Retzius Cells, and Cortical Evolution

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Further Reading Bar, I., Lambert de Rouvroit, C., and Goffinet, A. M. 2000. The evolution of cortical development. An hypothesis based on the role of the reelin signaling pathway. Trends Neurosci. 23, 633–638. Goffinet, A. M. 1983. The embryonic development of the cortical plate in reptiles: A comparative study in Emys orbicularis and Lacerta agilis. J. Comp. Neurol. 215, 437–452. Goffinet, A. M., Daumerie, C., Langerwerf, B., and Pieau, C. 1986. Neurogenesis in reptilian cortical structures: 3H-thymidine autoradiographic analysis. J. Comp. Neurol. 243, 106–116. Meyer, G., Perez-Garcia, C. G., Abraham, H., and Caput, D. 2002. Expression of p73 and reelin in the developing human cortex. J. Neurosci. 22, 4973–4986. Raff, R. A. 1996. The Shape of Life. Chicago University Press. Rakic, P. 2004. Neuroscience. Genetic control of cortical convolutions. Science 303, 1983–1984. Rice, D. S. and Curran, T. 2001. Role of the reelin signaling pathway in central nervous system development. Annu. Rev. Neurosci. 24, 1005–1039. Tissir, F. and Goffinet, A. M. 2003. Reelin and brain development. Nat. Rev. Neurosci. 4, 496–505.