Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Reelin and brain development

Key Points

  • Reeler mice were the first animal mutants to be described with malformations of the cerebral cortex. Interest in these mice increased further after the cloning of the affected gene, which was named reelin (Reln).

  • Neuronal migration is initially normal in the brains of reeler mice, but it seems that some cells do not recognize their proper location and orientation at the end of their migration pathway. The defect is most severe in the cerebral cortex, hippocampus and cerebellar cortex, but subtle anomalies have been identified at every location that has been searched.

  • Reln is secreted by some neurons, such as Cajal–Retzius cells in the cortical marginal zones, and cerebellar granule cells, and it acts through the extracellular milieu on neighbouring target cells to provide an architectonic signal.

  • Reception of the Reln signal requires the presence of at least one of two receptors of the lipoprotein receptor family — the very-low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor type 2 (ApoER2). The signal is relayed by tyrosine phosphorylation of an intracellular adaptor named Disabled 1 (Dab1).

  • The Reln protein is cleaved at two main locations, and almost no full length Reln is detected in adult and embryonic brain extracts and body fluids. The main polypeptides are the amino-terminal 180 kDa and the carboxy-terminal 100 kDa fragments. However, the central region of Reln is essential for receptor binding and triggering of Dab1 phosphorylation.

  • The dissection of the Reln signaling network is proving to be difficult, because it does not seem to conform to any known model. However, progress was recently made on two fronts — the interactions between Reln and its receptors, and the characterization of tyrosine kinases that have been implicated in Dab1 phosphorylation.

  • The cellular action of Reln during radial neuronal migration is unclear, but it has been proposed that it might act as a 'stop' signal for neurons at the end of their migration pathway. It has also been indicated that it regulates nucleokinesis — the progression of the nucleus into the cytoplasmic furrow that results from extension of the leading edge of a migrating cell.

Abstract

Over the last 50 years, the reeler mutant mouse has become an important model for studying normal and abnormal development in the cerebral cortex and other regions of the brain. However, we are only just beginning to understand the actions of reelin — the protein that is affected by the reeler mutation — at the molecular and cellular level. This review discusses the most recent advances in this research field, and considers the merits of the various models that have been put forward to explain how reelin works.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Schematic view of early cortical development in mice.
Figure 2: Photomicrography of the normal and reeler telencephalon at embryonic day 14.5.
Figure 3: The reeler phenotype in other brain regions.
Figure 4: Schema of the reelin protein.
Figure 5: The partners of reelin signalling.
Figure 6: Putative mechanism of action of Reelin.

Similar content being viewed by others

References

  1. Falconer, D. S. Two new mutants, Trembler and Reeler, with neurological actions in the house mouse. J. Genet. 50, 192–201 (1951).

    Article  CAS  PubMed  Google Scholar 

  2. D'Arcangelo, G. et al. A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 374, 719–723 (1995). This landmark paper reports the cloning of Reln. The authors took advantage of a reeler allele produced by a unique transgenic insertion, allowing cloning of the gene inactivated by the translocation breakpoint.

    Article  CAS  PubMed  Google Scholar 

  3. Lambert de Rouvroit, C. & Goffinet, A. M. The reeler mouse as a model of brain development. Adv. Anat. Embryol. Cell Biol. 150, 1–106 (1998). This booklet comprehensively covers the history of the Reln field and studies on reeler and related mice, from 1950, when the gene was cloned, to 1998. It could be consulted by investigators who wish to initiate work on this problem.

    Article  CAS  PubMed  Google Scholar 

  4. Rice, D. S. & Curran, T. Role of the reelin signaling pathway in central nervous system development. Annu. Rev. Neurosci. 24, 1005–1039 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Andersen, T. E., Finsen, B., Goffinet, A. M., Issinger, O. G. & Boldyreff, B. A reeler mutant mouse with a new, spontaneous mutation in the reelin gene. Brain Res. Mol. Brain Res. 105, 153–156 (2002). This work is important as it demonstrates biochemically the direct binding of Reln to lipoprotein receptors, thereby confirming the genetic data of Trommsdorf et al . described in reference 11.

    Article  CAS  PubMed  Google Scholar 

  6. Hong, S. E. et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nature Genet. 26, 93–96 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Sheldon, M. et al. Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice. Nature 389, 730–733 (1997). This work reported the identification of Dab1 mutations in scrambler and yotari mice, two mutants with a reeler -like phenotype.

    Article  CAS  PubMed  Google Scholar 

  8. Ware, M. L. et al. Aberrant splicing of a mouse disabled homolog, mdab1, in the scrambler mouse. Neuron 19, 239–249 (1997). This paper reported the positional cloning of the scrambler mutation, with identification of mutations in the Dab1 gene.

    Article  CAS  PubMed  Google Scholar 

  9. Howell, B. W., Hawkes, R., Soriano, P. & Cooper, J. A. Neuronal position in the developing brain is regulated by mouse disabled-1. Nature 389, 733–737 (1997). This paper reported the knockout of the Dab1 gene and showed that it mimics the reeler phenotype, thereby establishing the key role of the Dab1 adaptor. Together with references 7 and 8, it established the position of Dab1 in the Reln pathway.

    Article  CAS  PubMed  Google Scholar 

  10. Hiesberger, T. et al. Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation. Neuron 24, 481–489 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Trommsdorff, M. et al. Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell 97, 689–701 (1999). This paper showed that mice with mutations in the VLDLR and ApoER2 genes have a reeler -like phenotype, whereas single mutants have only subtle anomalies of brain development. This demonstrated the importance of lipoprotein receptors in the pathway.

    Article  CAS  PubMed  Google Scholar 

  12. Rice, D. S. et al. The reelin pathway modulates the structure and function of retinal synaptic circuitry. Neuron 31, 929–941 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Yip, J. W., Yip, Y. P., Nakajima, K. & Capriotti, C. Reelin controls position of autonomic neurons in the spinal cord. Proc. Natl Acad. Sci. USA 97, 8612–8616 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Meyer, G., Lambert de Rouvroit, C., Goffinet, A. M. & Wahle, P. Disabled-1 mRNA and protein expression in developing human cortex. Eur. J. Neurosci. 17, 517–525 (2003).

    Article  PubMed  Google Scholar 

  15. Rice, D. S. et al. Disabled-1 acts downstream of Reelin in a signaling pathway that controls laminar organization in the mammalian brain. Development 125, 3719–3729 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. Kobold, D. et al. Expression of reelin in hepatic stellate cells and during hepatic tissue repair: a novel marker for the differentiation of HSC from other liver myofibroblasts. J. Hepatol. 36, 607–613 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Buchaille, R., Couble, M. L., Magloire, H. & Bleicher, F. A substractive PCR-based cDNA library from human odontoblast cells: identification of novel genes expressed in tooth forming cells. Matrix Biol. 19, 421–430 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Smalheiser, N. R. et al. Expression of reelin in adult mammalian blood, liver, pituitary pars intermedia, and adrenal chromaffin cells. Proc. Natl Acad. Sci. USA 97, 1281–1286 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ikeda, Y. & Terashima, T. Expression of reelin, the gene responsible for the reeler mutation, in embryonic development and adulthood in the mouse. Dev. Dyn. 210, 157–172 (1997).

    Article  CAS  PubMed  Google Scholar 

  20. Bar, I. et al. A YAC contig containing the reeler locus with preliminary characterization of candidate gene fragments. Genomics 26, 543–549 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. DeSilva, U. et al. The human reelin gene: isolation, sequencing, and mapping on chromosome 7. Genome Res. 7, 157–164 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Royaux, I., Lambert de Rouvroit, C., D'Arcangelo, G., Demirov, D. & Goffinet, A. M. Genomic organization of the mouse reelin gene. Genomics 46, 240–250 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Tremolizzo, L. et al. An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability. Proc. Natl Acad. Sci. USA 99, 17095–17100 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chen, Y., Sharma, R. P., Costa, R. H., Costa, E. & Grayson, D. R. On the epigenetic regulation of the human reelin promoter. Nucleic Acids Res. 30, 2930–2939 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chen, M. L., Chen, S. Y., Huang, C. H. & Chen, C. H. Identification of a single nucleotide polymorphism at the 5' promoter region of human reelin gene and association study with schizophrenia. Mol. Psychiatry 7, 447–448 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Bar, I., Lambert de Rouvroit, C. & Goffinet, A. M. The evolution of cortical development. An hypothesis based on the role of the Reelin signaling pathway. Trends Neurosci. 23, 633–638 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Lambert de Rouvroit, C., Bernier, B., Royaux, I., de Bergeyck, V. & Goffinet, A. M. Evolutionarily conserved, alternative splicing of reelin during brain development. Exp. Neurol. 156, 229–238 (1999).

    Article  CAS  PubMed  Google Scholar 

  28. D'Arcangelo, G. et al. Reelin is a secreted glycoprotein recognized by the CR-50 monoclonal antibody. J. Neurosci. 17, 23–31 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. de Bergeyck, V., Naerhuyzen, B., Goffinet, A. M. & Lambert de Rouvroit, C. A panel of monoclonal antibodies against reelin, the extracellular matrix protein defective in reeler mutant mice. J. Neurosci. Methods 82, 17–24 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Ogawa, M. et al. The reeler gene-associated antigen on Cajal–Retzius neurons is a crucial molecule for laminar organization of cortical neurons. Neuron 14, 899–912 (1995). Before the Reln gene was cloned, these authors generated the CR50 antibody against Cajal–Retzius cells by immunizing reeler mice with brain extracts. The antibody was later shown to recognize an N-terminal epitope of Reln and is thought to perturb the function of Reln.

    Article  CAS  PubMed  Google Scholar 

  31. Lambert de Rouvroit, C. et al. Reelin, the extracellular matrix protein deficient in reeler mutant mice, is processed by a metalloproteinase. Exp. Neurol. 156, 214–217 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Herz, J. & Bock, H. H. Lipoprotein receptors in the nervous system. Annu. Rev. Biochem. 71, 405–434 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Nimpf, J. & Schneider, W. J. From cholesterol transport to signal transduction: low density lipoprotein receptor, very low density lipoprotein receptor, and apolipoprotein E receptor-2. Biochim. Biophys. Acta 1529, 287–298 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Rudenko, G. et al. Structure of the LDL receptor extracellular domain at endosomal pH. Science 298, 2337–2339 (2002).

    Article  CAS  Google Scholar 

  35. Stockinger, W. et al. The reelin receptor ApoER2 recruits JNK-interacting proteins-1 and-2. J. Biol. Chem. 275, 25625–25632 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Howell, B. W., Lanier, L. M., Frank, R., Gertler, F. B. & Cooper, J. A. The disabled 1 phosphotyrosine-binding domain binds to the internalization signals of transmembrane glycoproteins and to phospholipids. Mol. Cell. Biol. 19, 5179–5188 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. D'Arcangelo, G. et al. Reelin is a ligand for lipoprotein receptors. Neuron 24, 471–479 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Benhayon, D., Magdaleno, S. & Curran, T. Binding of purified Reelin to ApoER2 and VLDLR mediates tyrosine phosphorylation of Disabled-1. Brain Res. Mol. Brain Res. 112, 33–45 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Boucher, P. et al. Platelet-derived growth factor mediates tyrosine phosphorylation of the cytoplasmic domain of the low Density lipoprotein receptor-related protein in caveolae. J. Biol. Chem. 277, 15507–15513 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Riddell, D. R., Sun, X. M., Stannard, A. K., Soutar, A. K. & Owen, J. S. Localization of apolipoprotein E receptor 2 to caveolae in the plasma membrane. J. Lipid Res. 42, 998–1002 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Kojima, T., Nakajima, K. & Mikoshiba, K. The disabled 1 gene is disrupted by a replacement with L1 fragment in yotari mice. Brain Res. Mol. Brain Res. 75, 121–127 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Howell, B. W., Herrick, T. M. & Cooper, J. A. Reelin-induced tryosine phosphorylation of disabled 1 during neuronal positioning. Genes Dev. 13, 643–648 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Keshvara, L., Benhayon, D., Magdaleno, S. & Curran, T. Identification of reelin-induced sites of tyrosyl phosphorylation on disabled 1. J. Biol. Chem. 276, 16008–16014 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Lambert de Rouvroit, C. & Goffinet, A. M. Cloning of human DAB1 and mapping to chromosome 1p31-p32. Genomics 53, 246–247 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. Bar, I., Tissir, F., Lambert De Rouvroit, C., De Backer, O. & Goffinet, A. M. The gene encoding disabled-1 (DAB1), the intracellular adaptor of the reelin pathway, reveals unusual complexity in human and mouse. J. Biol. Chem., 278, 5802-5812, (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Howell, B. W., Herrick, T. M., Hildebrand, J. D., Zhang, Y. & Cooper, J. A. Dab1 tyrosine phosphorylation sites relay positional signals during mouse brain development. Curr. Biol. 10, 877–885 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Herrick, T. M. & Cooper, J. A. A hypomorphic allele of dab1 reveals regional differences in reelin-Dab1 signaling during brain development. Development 129, 787–796 (2002). This paper shows that a Dab1 null mutation can be rescued fully by a knock-in of the normal Dab1 cDNA, and partially by a partial cDNA that contains the PI/PTB domain and the adjacent region that encodes key Tyr residues, but not by a cDNA in which five Tyr residues are replaced by Phe.

    Article  CAS  PubMed  Google Scholar 

  48. Keshvara, L., Magdaleno, S., Benhayon, D. & Curran, T. Cyclin-dependent kinase 5 phosphorylates disabled 1 independently of Reelin signaling. J. Neurosci. 22, 4869–4877 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kubo, K., Mikoshiba, K. & Nakajima, K. Secreted Reelin molecules form homodimers. Neurosci. Res. 43, 381–388 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Utsunomiya-Tate, N. et al. Reelin molecules assemble together to form a large protein complex, which is inhibited by the function-blocking CR-50 antibody. Proc. Natl Acad. Sci. USA 97, 9729–9734 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jossin, Y. et al. The Reelin signaling pathway: some recent developments. Cereb. Cortex, 13, 627-633 (2003).

    Article  PubMed  Google Scholar 

  52. Miyata, T., Nakajima, K., Mikoshiba, K. & Ogawa, M. Regulation of Purkinje cell alignment by reelin as revealed with CR-50 antibody. J. Neurosci. 17, 3599–3609 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Nakajima, K., Mikoshiba, K., Miyata, T., Kudo, C. & Ogawa, M. Disruption of hippocampal development in vivo by CR-50 mAb against reelin. Proc. Natl Acad. Sci. USA. 94, 8196–8201 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bock, H. H. & Herz, J. Reelin activates SRC family tyrosine kinases in neurons. Curr. Biol. 13, 18–26 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Arnaud, L., Ballif, B. A., Forster, E. & Cooper, J. A. Fyn tyrosine kinase is a critical regulator of disabled-1 during brain development. Curr. Biol. 13, 9–17 (2003). References 54 and 55 show that tyrosine kinases of the Src family, particularly Fyn and Yes, are key elements in the transduction of the Reln signal, and that they mediate Dab1 tyrosine phosphorylation. These two studies also indicate that there is redundancy among this kinase family.

    Article  CAS  PubMed  Google Scholar 

  56. Senzaki, K., Ogawa, M. & Yagi, T. Proteins of the CNR family are multiple receptors for Reelin. Cell 99, 635–647 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Weiss, A. & Littman, D. R. Signal transduction by lymphocyte antigen receptors. Cell 76, 263–274 (1994).

    Article  CAS  PubMed  Google Scholar 

  58. Zhang, Z., Coomans, C. & David, G. Membrane heparan sulfate proteoglycan-supported FGF2-FGFR1 signaling: evidence in support of the 'cooperative end structures' model. J. Biol. Chem. 276, 41921–41929 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Loukinova, E. et al. Platelet-derived growth factor (PDGF)-induced tyrosine phosphorylation of the low density lipoprotein receptor-related protein (LRP). Evidence for integrated co-receptor function between LRP and the PDGF. J. Biol. Chem. 277, 15499–15506 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Pinson, K. I., Brennan, J., Monkley, S., Avery, B. J. & Skarnes, W. C. An LDL-receptor-related protein mediates Wnt signalling in mice. Nature 407, 535–538 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Meyer, G., De Rouvroit, C. L., Goffinet, A. M. & Wahle, P. Disabled-1 mRNA and protein expression in developing human cortex. Eur. J. Neurosci. 17, 517–525 (2003).

    Article  PubMed  Google Scholar 

  62. Hack, I., Bancila, M., Loulier, K., Carroll, P. & Cremer, H. Reelin is a detachment signal in tangential chain-migration during postnatal neurogenesis. Nature Neurosci. 5, 939–945 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Kim, H. M. et al. Reelin function in neural stem cell biology. Proc. Natl Acad. Sci. USA 99, 4020–4025 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Forster, E. et al. Reelin, Disabled 1, and β1 integrins are required for the formation of the radial glial scaffold in the hippocampus. Proc. Natl Acad. Sci. USA 99, 13178–13183 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Tissir, F., Lambert de Rouvroit, C., Sire, J. Y., Meyer, G. & Goffinet, A. M. Reelin expression during embryonic brain development in Crocodylus niloticus. J. Comp. Neurol. 457, 250–262 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Haas, C. A. et al. Role for reelin in the development of granule cell dispersion in temporal lobe epilepsy. J. Neurosci. 22, 5797–5802 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Perez-Costas, E. et al. Reelin immunoreactivity in the larval sea lamprey brain. J. Chem. Neuroanat. 23, 211–221 (2002).

    Article  CAS  PubMed  Google Scholar 

  68. Costagli, A., Kapsimali, M., Wilson, S. W. & Mione, M. Conserved and divergent patterns of Reelin expression in the zebrafish central nervous system. J. Comp. Neurol. 450, 73–93 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Rice, D. S. & Curran, T. Disabled-1 is expressed in type AII amacrine cells in the mouse retina. J. Comp. Neurol. 424, 327–338 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Pearlman, A. L., Faust, P. L., Hatten, M. E. & Brunstrom, J. E. New directions for neuronal migration. Curr. Opin. Neurobiol. 8, 45–54 (1998).

    Article  CAS  PubMed  Google Scholar 

  71. Frotscher, M. Cajal-Retzius cells, Reelin, and the formation of layers. Curr. Opin. Neurobiol. 8, 570–575 (1998).

    Article  CAS  PubMed  Google Scholar 

  72. Lambert de Rouvroit, C. & Goffinet, A. M. Neuronal migration. Mech. Dev. 105, 47–56 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Malatesta, P., Hartfuss, E. & Gotz, M. Isolation of radial glial cells by fluorescent-activated cell sorting reveals a neuronal lineage. Development 127, 5253–5263 (2000).

    Article  CAS  PubMed  Google Scholar 

  74. Noctor, S. C., Flint, A. C., Weissman, T. A., Dammerman, R. S. & Kriegstein, A. R. Neurons derived from radial glial cells establish radial units in neocortex. Nature 409, 714–720 (2001).

    Article  CAS  PubMed  Google Scholar 

  75. Miyata, T., Kawaguchi, A., Okano, H. & Ogawa, M. Asymmetric inheritance of radial glial fibers by cortical neurons. Neuron 31, 727–741 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Nadarajah, B., Brunstrom, J. E., Grutzendler, J., Wong, R. O. & Pearlman, A. L. Two modes of radial migration in early development of the cerebral cortex. Nature Neurosci. 4, 143–150 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Nadarajah, B. & Parnavelas, J. G. Modes of neuronal migration in the developing cerebral cortex. Nature Rev. Neurosci. 3, 423–432 (2002).

    Article  CAS  Google Scholar 

  78. Del Rio, J. A. et al. A role for Cajal–Retzius cells and reelin in the development of hippocampal connections. Nature 385, 70–74 (1997).

    Article  CAS  PubMed  Google Scholar 

  79. Deller, T. et al. The hippocampus of the reeler mutant mouse: fiber segregation in area CA1 depends on the position of the postsynaptic target cells. Exp. Neurol. 156, 254–267 (1999).

    Article  CAS  PubMed  Google Scholar 

  80. Jossin, Y. & Goffinet, A. M. Reelin does not directly influence axonal growth. J. Neurosci. 21, RC183 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Teillon, S. M., Yiu, G. & Walsh, C. A. Reelin is expressed in the accessory olfactory system, but is not a guidance cue for vomeronasal axons. Brain Res. Dev. Brain Res. 140, 303–307 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Walsh, C. A. & Goffinet, A. M. Potential mechanisms of mutations that affect neuronal migration in man and mouse. Curr. Opin. Genet. Dev. 10, 270–274 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Phelps, P. E., Rich, R., Dupuy-Davies, S., Rios, Y. & Wong, T. Evidence for a cell-specific action of Reelin in the spinal cord. Dev. Biol. 244, 180–198 (2002).

    Article  CAS  PubMed  Google Scholar 

  84. Magdaleno, S., Keshvara, L. & Curran, T. Rescue of ataxia and preplate splitting by ectopic expression of Reelin in reeler mice. Neuron 33, 573–586 (2002). This is the first attempt to rescue the reeler phenotype by transgenesis with a Reln cDNA under the control of the nestin promoter. A partial rescue was obtained, even though Reln was expressed ectopically in the ventricular zone instead of Cajal–Retzius cells. This provides an argument for an indirect action of Reln that would make neurons responsive to another signal in the marginal zone.

    Article  CAS  PubMed  Google Scholar 

  85. Hammond, V., Howell, B., Godinho, L. & Tan, S. S. Disabled-1 functions cell autonomously during radial migration and cortical layering of pyramidal neurons. J. Neurosci. 21, 8798–8808 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Yang, H., Jensen, P. & Goldowitz, D. The community effect and Purkinje cell migration in the cerebellar cortex: analysis of scrambler chimeric mice. J. Neurosci. 22, 464–470 (2002). By studying chimaeras produced by aggregation of normal and Dab1 mutant morulae, these authors show that some actions of Dab1 are not fully explained by a cell-autonomous effect of this intracellular adaptor, implying a 'community effect' that hints at the importance of cell–cell interaction events.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Goffinet, A. M. An early development defect in the cerebral cortex of the reeler mouse. A morphological study leading to a hypothesis concerning the action of the mutant gene. Anat. Embryol. (Berl.) 157, 205–216 (1979).

    Article  CAS  Google Scholar 

  88. Dulabon, L. et al. Reelin binds α3β1 integrin and inhibits neuronal migration. Neuron 27, 33–44 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Costa, E., Davis, J., Pesold, C., Tueting, P. & Guidotti, A. The heterozygote reeler mouse as a model for the development of a new generation of antipsychotics. Curr. Opin. Pharmacol. 2, 56–62 (2002).

    Article  CAS  PubMed  Google Scholar 

  90. Fatemi, S. H., Kroll, J. L. & Stary, J. M. Altered levels of Reelin and its isoforms in schizophrenia and mood disorders. Neuroreport 12, 3209–3215 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Guidotti, A., Pesold, C. & Costa, E. New neurochemical markers for psychosis: a working hypothesis of their operation. Neurochem. Res. 25, 1207–1218 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Impagnatiello, F. et al. A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc. Natl Acad. Sci. USA 95, 15718–15723 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Fatemi, S. H. The role of Reelin in pathology of autism. Mol. Psychiatry 7, 919–920 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Andres, C. Molecular genetics and animal models in autistic disorder. Brain Res. Bull. 57, 109–119 (2002).

    Article  CAS  PubMed  Google Scholar 

  95. Zhang, H. et al. Reelin gene alleles and susceptibility to autism spectrum disorders. Mol. Psychiatry 7, 1012–1017 (2002).

    Article  CAS  PubMed  Google Scholar 

  96. Stokstad, E. Development. New hints into the biological basis of autism. Science 294, 34–37 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Persico, A. M. et al. Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Mol. Psychiatry 6, 150–159 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Krebs, M. O. et al. Absence of association between a polymorphic GGC repeat in the 5' untranslated region of the reelin gene and autism. Mol. Psychiatry 7, 801–804 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Tueting, P. et al. The phenotypic characteristics of heterozygous reeler mouse. Neuroreport 10, 1329–1334 (1999).

    Article  CAS  PubMed  Google Scholar 

  100. Lewis, D. A. & Levitt, P. Schizophrenia as a disorder of neurodevelopment. Annu. Rev. Neurosci. 25, 409–432 (2002).

    Article  CAS  PubMed  Google Scholar 

  101. Ohkubo, N. et al. Apolipoprotein E and Reelin ligands modulate tau phosphorylation through an apolipoprotein E receptor/disabled-1/glycogen synthase kinase-3β cascade. FASEB J. 17, 295–297 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Homayouni, R., Rice, D. S., Sheldon, M. & Curran, T. Disabled-1 binds to the cytoplasmic domain of amyloid precursor-like protein 1. J. Neurosci. 19, 7507–7515 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Ohshima, T. & Mikoshiba, K. Reelin signaling and Cdk5 in the control of neuronal positioning. Mol. Neurobiol. 26, 153–166 (2002).

    Article  CAS  PubMed  Google Scholar 

  104. Ko, J. et al. p35 and p39 are essential for cyclin-dependent kinase 5 function during neurodevelopment. J. Neurosci. 21, 6758–6771 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Tseng, H. C., Zhou, Y., Shen, Y. & Tsai, L. H. A survey of Cdk5 activator p35 and p25 levels in Alzheimer's disease brains. FEBS Lett. 523, 58–62 (2002).

    Article  CAS  PubMed  Google Scholar 

  106. Beffert, U. et al. Reelin-mediated signaling locally regulates protein kinase B/Akt and glycogen synthase kinase 3β. J. Biol. Chem. 277, 49958–49964 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Brich, J. et al. Genetic modulation of tau phosphorylation in the mouse. J. Neurosci. 23, 187–192 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We wish to thank C. Lambert de Rouvroit for her help in the preparation of this review, as well as I. Bar, Y. Jossin and N. Ignatova for discussions and inclusion of unpublished results. We apologize to colleagues for the inevitable selection of citations due to space limitations. This work was supported by the Fondation Médicale Reine Elisabeth, and by the fifth framework program of the European Union.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to André M. Goffinet.

Related links

Related links

DATABASES

LocusLink

ApoER2

Dab1

Fyn

Reln

VLDLR

Omim

autism

Glossary

LISSENCEPHALY

Literally meaning 'smooth brain'. Lissencephaly is a human brain disorder that is characterized by absence or reduction of the cerebral convolutions.

VENTRICULAR ZONE

The proliferative inner layer of the developing brain and spinal cord.

SUBVENTRICULAR ZONE

A layer of cells in the developing brain that is generated by the migration of neuroblasts from the adjoining ventricular zone.

RHOMBIC LIP

A specialized germinal matrix located at the posterior edge of the cerebellar anlage that gives rise to the granule cells of the cerebellum.

TATA BOX

A DNA sequence with the consensus TATAAAA that is present in many eukaryotic gene promoters and specifies the site where transcription is initiated.

5′RACE

(5′ rapid amplification of cDNA ends). RACE is a PCR-based method for amplifying unknown cDNA sequences by using primers that correspond to a known sequence.

ALTERNATIVE SPLICING

During splicing, introns are excised from RNA after transcription and the cut ends are rejoined to form a continuous message. Alternative splicing allows the production of different messages from the same DNA molecule.

METALLOPROTEINASE

A proteinase that has a metal ion at its active site.

β-PROPELLER

A protein domain that consists of an array of β-sheet motifs, which are configured in a ring to resemble the blades of a propeller.

CAVEOLAE

Specialized rafts that contain the protein caveolin and form a flask-shaped, cholesterol-rich invagination of the plasma membrane. They might mediate the uptake of some extracellular materials and are probably involved in cell signalling.

LIPID RAFTS

Cholesterol-rich lipid domains that are used to transport proteins around the cell and to organize signalling complexes on the membrane.

HYPOMORPHIC ALLELE

An allele that results in a reduction, but not the elimination, of wild-type levels of gene product or activity, often causing a less severe phenotype than a loss-of-function (or null) allele.

HEPARAN SULPHATE

A glycosaminoglycan that consists of repeated units of hexuronic acid and glucosamine residues. It usually attaches to proteins through a xylose residue to form proteoglycans.

YEAST TWO-HYBRID SCREENS

System used to determine the existence of direct interactions between proteins. It involves the use of plasmids that encode two hybrid proteins; for example, one of them is fused to the GAL4 DNA-binding domain and the other one is fused to the GAL4 activation domain. The two proteins are expressed together in yeast and, if they interact, then the resulting complex will drive the expression of a reporter gene, commonly β-galactosidase.

SOMAL TRANSLOCATION

Displacement of the cell body, as opposed to migration of the whole cell.

BLASTOCYST INJECTION

The introduction of embryonic stem cells into a blastocyst-stage embryo of a different genotype to generate a chimaeric embryo.

MORULA AGGREGATION

A technique in which the cells of two different embryos at the morula stage (when the embryo comprises a solid ball of cells) are dissociated, mixed and allowed to recombine to generate a chimaeric embryo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tissir, F., Goffinet, A. Reelin and brain development. Nat Rev Neurosci 4, 496–505 (2003). https://doi.org/10.1038/nrn1113

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn1113

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing