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PERSPECTIVE
Neurogenetics Laboratory, Department of Neurosciences, University of California at San Diego, La Jolla, California 92093, USA
In 1951, Douglas Scott Falconer first described the reeler spontaneous mutant mouse (Falconer 1951
). In those mice, cortical neurons are generated normally but migrate abnormally, resulting in an inversion of the cortical laminar organization, with later-born neurons remaining in the deeper layers of the cortex. Forty-four years later, D’Arcangelo et al. (1995) identified the causative gene Rln and the encoded protein Reelin. Reelin pathway mutants, and particularly mice with mutations of its intracellular effector Dab1 (Disabled-1), probably represent the most-studied phenotype of altered neuronal migration. The observations that mutations of Dab1 phenocopy the Rln mutation, and that Dab1 is up-regulated in reeler mice suggested the existence of a negative feedback loop in Reelin signaling via the regulation of Dab1 levels. In the previous issue of Genes & Development, Feng et al. (2007) presented the first coherent model to explain the mechanism of Reelin-mediated Dab1 down-regulation. They proposed that Reelin both activates and down-regulates its effector Dab1, first by inducing its phosphorylation, which then causes its targeting by an E3 ubiquitin ligase complex (EBC) containing SOCS family proteins and Cullin5 (Cul5). The impairment of this down-regulation mechanism in vivo leads to a unique phenotype in the cortex where neurons migrate past their target layer.
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The known side of Reelin/Dab1 signaling |
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; Hiesberger et al. 1999; Trommsdorff et al. 1999; Kubo et al. 2002; Strasser et al. 2004). The binding of Reelin to its receptors induces the tyrosine phosphorylation of the cytoplasmic adaptor protein Dab1, which interacts with the conserved motif NPxY in the cytoplasmic tails of VLDLR and ApoER2 (Trommsdorff et al. 1998; Howell et al. 1999).
In addition, Dab1 binds to and is phophorylated by nonreceptor tyrosine kinases from the Src family (SFK): Src and Fyn (Arnaud et al. 2003a; Kuo et al. 2005). Noticeably, the mouse Dab1 was originally identified in a yeast two-hybrid screen for Src-interacting proteins (Howell et al. 1997). Src and Fyn are activated (phosphorylated) through the Reelin pathway, and thus together, Dab1 tyrosine phosphorylation and SFK phosphorylation are two interdependent mechanisms that are part of a positive feedback loop (Arnaud et al. 2003b; Bock and Herz 2003).
In the developing cortex, Reelin is specifically expressed by horizontally orientated Cajal-Retzius neurons located in the preplate before its splitting and then in the outermost layer of the cortex (the marginal zone of the developing brain, becoming layer I of the mature brain) (Fig. 1; D’Arcangelo et al. 1995; Ogawa et al. 1995). On the other hand, ApoER2, VLDLR, and Dab1 are expressed by both cortical neurons and radial glia cells supporting their migration (Forster et al. 2002; Frotscher et al. 2003; Hartfuss et al. 2003; Luque et al. 2003). Strikingly, mutations of both VLDLR and ApoER2, of Dab1 and particularly point mutations at five Dab1 tyrosine phosphorylation sites (Dab15F mutation of Tyr185, Tyr198, Tyr200, Tyr220, and Tyr232), or mutation of both SFK Src and Fyn result in a phenocopy of the reeler phenotype, with a failure to split the preplate as well as inverting cortical layering (Howell et al. 1997, 2000; Sheldon et al. 1997; Benhayon et al. 2003; Kuo et al. 2005), validating that they participate in a common signaling pathway regulating cortical neuronal migration.
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Down-regulating Dab1 |
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; Rice et al. 1998; Trommsdorff et al. 1999; Arnaud et al. 2003b; Bock and Herz 2003; Kuo et al. 2005). Interestingly, this Dab1 down-regulation happens post-transcriptionaly, as Dab1 mRNA expression is unchanged in the deficient cells (Rice et al. 1998). Several recent advances provide further understanding of the mechanism of this post-transcriptional down-regulation of Dab1. Arnaud et al. (2003a) and Bock et al. (2004) previously showed in primary neuronal cultures that Dab1 is down-regulated through polyubiquitination and targeting to the proteasome in the presence of Reelin, and that this modification requires tyrosine phosphorylation of Dab1. Moreover, inhibition of Dab1 tyrosine phosphorylation and inhibition of SFK activation blocks Dab1 down-regulation (Arnaud et al. 2003b; Bock et al. 2004; Kuo et al. 2005). Feng et al. (2007) identified two critical Dab1 tyrosine phosphorylation sites (primary Tyr198, and also Tyr185), both at YQxI sequences, essential for the Dab1 degradation in response to Reelin, in an embryonic cortical neuron culture system. Tyr198 had been formerly predicted as a potential Reelin-induced Dab1 phosphorylation site by a Web-based PESTfind algorithm; however, the same method failed to identify Tyr185, but instead predicted the importance of Tyr220 (Bock et al. 2004). Among the potential ubiquitin ligase complexes targeting Dab1 in the presence of Reelin, the E3 ligase Cbl seemed a good candidate to mediate Dab1 degradation. Indeed, Cbl is abundantly expressed in cortical neurons and contains a phospho-tyrosine recognition domain comprising an EF-hand and a SH2-like structure through which it binds phospho-tyrosine residues, followed by a hydrophobic residue at pY + 4 (fourth residue after the phospho-tyrosine). These are similar to the motifs found at phosphorylation sites Tyr185 and Tyr198 of Dab1 (Lupher et al. 1997; Meng et al. 1999). Previous studies showed that Cbl can ubiquitinate Dab1, at least in transfected COS7 cells (Suetsugu et al. 2004). However, Arnaud et al. (2003a) failed to detect complexed Cbl and Dab1 by immunoprecipitation, or tyrosine-phosphorylated Cbl in Reelin-stimulated primary neuron cultures, which are required for its activation as an E3 ligases (Levkowitz et al. 1999). Additionally, targeted deletion of Cbl in mice failed to induce neurodevelopmental defects reminiscent of the reeler phenotype (Thien and Langdon 2001).
Feng et al. (2007) identifed another type of EBC potentially regulating Dab1 in vivo. They also used nonneuronal cells lines such as COS7, in which Dab1, when coexpressed with Fyn and Src, is known to be constitutively tyrosine phophorylated but not degraded. This suggests that a component of the degradation machinery targeting phospho-tyrosine Dab1 is absent or limiting in this in vitro system, which thus makes it particularly adapted for a candidate approach. Feng et al. (2007) tested several E3 ubiquitin ligases in this nonneuronal cell system and show that the SOCS1–3 ligases can bind to Dab1, and induce Tyr185 or Tyr198 phophorylated Dab1 degradation, in a Fyn-dependent manner. Interestingly, they also tested Cbl in this assay and show that it fails to induce Dab1 degradation, further invalidating the Cbl implication hypothesis. Because many SOCS proteins are expressed during brain development (among them SOCS1–3) and might be functionally redundant, Feng et al. (2007) chose to study the consequence of the inactivation of another component of the SOCS-containing EBC on Reelin-induced degradation of Dab1: the cullin Cul5 (Petroski and Deshaies 2005). Cul5 recently has been shown and confirmed in the study by Feng et al. (2007) to be expressed in mouse cortical neurons (Lein et al. 2007), but its role was so far completely unknown. Feng et al. (2007) showed that in cultured cortical neurons, Cul5 binds to Dab1, and that Cul5 knockdown specifically protects Dab1 from Reelin-induced degradation. Noticeably, Dab1 interaction with ubiquitin ligases may also have other biological significance. Dab1 has been shown to interact with the E3 ubiquitin ligase Siah-1A in yeast two-hybrid assays and coimmunoprecipitation experiments in 293T cells. But in that case, Dab1–Siah1 binding induces the inhibition of Siah-1A ubiquitinating activity (Park et al. 2003). Thus, one might wonder if Dab1 could additionally regulate EBC containing SOCS and Cul5 as well, adding a step to the complexity of this Reelin feedback loop.
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Overmigration: when Dab1 down-regulation fails to occur |
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showed for the first time the in vivo consequences of a failure of Dab1 down-regulation on neuronal migration. Bock et al. (2004) showed that blocking proteasome activity disturbs the proper organization of a cultured embryonic cortical plate, suggesting very indirectly that Dab1 degradation is important for its role in regulating neuronal migration. In this paper, Feng et al. (2007) observed that Cul5 knockdown in the cortex leads to an increased Dab1 level in vivo and to a unique migration defect. Cul5 knockdown neurons are located more superficially within the cortical plate relative to control neurons, and partly intrude into the marginal zone. This is the first description of such a phenotype of "overmigration" that clearly differs from the similarly named phenotype of POMGnT1 (O-mannose 
31,2-N-acetyl- glucosaminyl-transferase 1)-deficient mice, in which cortical neurons overmigrate past the neural boundary through breaches in the pia matter caused by overgrown radial glial endfeet (Hu et al. 2007). Interestingly, Cul5 knockdown neurons remain at the surface of the cortex, instead of being bypassed by younger neurons. This defect is partially rescued in vivo by the coelectroporation of Dab1 short hairpin RNA (shRNA). Furthermore Cul5 shRNA stops Dab1 degradation in vitro, validating that the overmigration is due to the inhibition of Dab1 degradation.
In the developing cortex, neurons migrate along the processes of their parental radial glia from the ventricular zone to the more superficial cortical layer and stop when they reach the marginal zone. Later-born neurons migrate through previously deposited neurons in cortical plate, leading to an inside-out lamination of the cortex (Fig. 1). The reeler phenotype displayed by Rln-deficient mice as well as mice deficient for VLDLR and ApoER2, Dab1, and Src and Fyn mutant show a rough inversion of the normal inside-out pattern of cortical migration and an excess of neurons in the normally cell-sparse marginal zone (Caviness and Sidman 1973; Howell et al. 1997, 2000; Sheldon et al. 1997; Benhayon et al. 2003; Kuo et al. 2005). The commonly accepted explanation for this phenotype is that the newly arrived neurons fail to penetrate the preplate and split it appropriately into the marginal zone and subplate, and cannot bypass previously deposited neurons and accumulate in an outside-in manner. Dab1 seems necessary to achieve the bypassing step in mosaic Dab1 wt; Dab1–/– embryos, mutant neurons lie below wild-type neurons (Hammond et al. 2001), and BrdU pulse-labeling experiments showed that Dab1 knockdown neurons accumulate in deep cortical plate and fail to pass their earlier-born siblings. Furthermore, neurons showing an abnormally high level of Dab1 migrate presumably faster through the cortical plate and stick to the marginal zone, preventing the passage of their siblings (Feng et al. 2007).
Overall, those results strongly suggest that Dab1 is necessary for neurons to cross previously deposited neuronal layers, and in turn, Dab1 should be down-regulated in neurons to properly terminate their migration and allow their siblings to bypass them. According to this hypothesis, a precise regulation of Dab1 levels should be required to control the precise location of the migration arrest. A threshold response to a gradient of a signaling molecule may be an efficient way to control a timely stop. However, maintaining a Reelin gradient within the cortical plate may be difficult as the depth and the layered organization of the cortical plate are continuously changing. A transcriptional mode of regulation implies latency of protein synthesis, which is slow in the case of Dab1, and of the protein half-life (12 h for Dab1) (Arnaud et al. 2003a), and thus is probably not an appropriate way to control a timely switch mechanism. Controlling expression level by regulating the degradation of a constantly synthesized protein, in a continuously responding neuron can constitute a very efficient method, in contrast. In migrating cortical neurons, Dab1 is constantly down-regulated (as implied by the fact that in reeler mice, the Dab1 level is increased throughout the depth of the cortex) (Arnaud et al. 2003a) via the Cul5/SOCS-containing E3 ligase complex. Dab1 regulation thus relies on the EBC activity, which may be rapidly controlled by protein complex assembly, to rapidly decrease Dab1 levels and definitively terminate neuronal migration.
Although knockdown results are very informative, essential complementary data would come from the analysis of the brain phenotype of Cul5-deficient mice. The inhibition of ubiquitination in cortical slices by Bock and Herz (2003) may provide some clues. Those slices showed massive disorganization of the layering; however, complementary cell tracing experiments, necessary to fully understand this phenotype, were not performed. In humans, cortical migration disorders caused by Reelin signaling deficiency lead to classical lissencephaly (Hong et al. 2000; Boycott et al. 2005; Chang et al. 2007; Zaki et al. 2007), a condition characterized by a paucity of cortical gyration, leading to severe epilepsy and mental retardation. Impairment of the down-regulation component of Reelin signaling is thus predicted to cause strong cortical developmental defects as well. A precise description of the phenotype of the Cul5-deficient mice cortex may pinpoint human brain abnormalities linked to this mechanism.
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Footnotes |
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E-MAIL jogleeson{at}ucsd.edu; FAX (858) 534-1437. 
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1622907
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TopThe known side of...Down-regulating Dab1Overmigration: when Dab1 down...AcknowledgmentsReferences |
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Arnaud, L., Ballif, B.A., Forster, E., and Cooper, J.A. 2003b. Fyn tyrosine kinase is a critical regulator of disabled-1 during brain development. Curr. Biol. 13: 9–17.[CrossRef][Medline]
Benhayon, D., Magdaleno, S., and Curran, T. 2003. Binding of purified Reelin to ApoER2 and VLDLR mediates tyrosine phosphorylation of Disabled-1. Brain Res. Mol. Brain Res. 112: 33–45.[Medline]
Bock, H.H. and Herz, J. 2003. Reelin activates SRC family tyrosine kinases in neurons. Curr. Biol. 13: 18–26.[CrossRef][Medline]
Bock, H.H., Jossin, Y., May, P., Bergner, O., and Herz, J. 2004. Apolipoprotein E receptors are required for reelin-induced proteasomal degradation of the neuronal adaptor protein Disabled-1. J. Biol. Chem. 279: 33471–33479.
Boycott, K.M., Flavelle, S., Bureau, A., Glass, H.C., Fujiwara, T.M., Wirrell, E., Davey, K., Chudley, A.E., Scott, J.N., McLeod, D.R., et al. 2005. Homozygous deletion of the very low density lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral simplification. Am. J. Hum. Genet. 77: 477–483.[CrossRef][Medline]
Caviness, V.S. and Sidman, R.L. 1973. Time of origin or corresponding cell classes in the cerebral cortex of normal and reeler mutant mice: An autoradiographic analysis. J. Comp. Neurol. 148: 141–151.[CrossRef][Medline]
Chang, B.S., Duzcan, F., Kim, S., Cinbis, M., Aggarwal, A., Apse, K.A., Ozdel, O., Atmaca, M., Zencir, S., Bagci, H., et al. 2007. The role of RELN in lissencephaly and neuropsychiatric disease. Am. J. Med. Genet. B Neuropsychiatr. Genet. 144: 58–63.[Medline]
D’Arcangelo, G., Miao, G.G., Chen, S.C., Soares, H.D., Morgan, J.I., and Curran, T. 1995. A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 374: 719–723.[CrossRef][Medline]
D’Arcangelo, G., Homayouni, R., Keshvara, L., Rice, D.S., Sheldon, M., and Curran, T. 1999. Reelin is a ligand for lipoprotein receptors. Neuron 24: 471–479.[CrossRef][Medline]
Falconer, D. 1951. 2 new mutants, trembler and reeler, with neurological actions in the house mouse (mus-musculus l). J. Genet. 50: 192–201.
Feng, L., Allen, N.S., Simo, S., and Cooper, J.A. 2007. Cullin 5 regulates Dab1 protein levels and neuron positioning during cortical development. Genes & Dev. 21: 2717–2730.
Forster, E., Tielsch, A., Saum, B., Weiss, K.H., Johanssen, C., Graus-Porta, D., Muller, U., and Frotscher, M. 2002. Reelin, Disabled 1, and 1 integrins are required for the formation of the radial glial scaffold in the hippocampus. Proc. Natl. Acad. Sci. 99: 13178–13183.
Frotscher, M., Haas, C.A., and Forster, E. 2003. Reelin controls granule cell migration in the dentate gyrus by acting on the radial glial scaffold. Cereb. Cortex 13: 634–640.
Hammond, V., Howell, B., Godinho, L., and Tan, S.S. 2001. disabled-1 functions cell autonomously during radial migration and cortical layering of pyramidal neurons. J. Neurosci. 21: 8798–8808.
Hartfuss, E., Forster, E., Bock, H.H., Hack, M.A., Leprince, P., Luque, J.M., Herz, J., Frotscher, M., and Gotz, M. 2003. Reelin signaling directly affects radial glia morphology and biochemical maturation. Development 130: 4597–4609.
Hiesberger, T., Trommsdorff, M., Howell, B.W., Goffinet, A., Mumby, M.C., Cooper, J.A., and Herz, J. 1999. 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.[CrossRef][Medline]
Hong, S.E., Shugart, Y.Y., Huang, D.T., Shahwan, S.A., Grant, P.E., Hourihane, J.O., Martin, N.D., and Walsh, C.A. 2000. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat. Genet. 26: 93–96.[CrossRef][Medline]
Howell, B.W., Hawkes, R., Soriano, P., and Cooper, J.A. 1997. Neuronal position in the developing brain is regulated by mouse disabled-1. Nature 389: 733–737.[CrossRef][Medline]
Howell, B.W., Lanier, L.M., Frank, R., Gertler, F.B., and Cooper, J.A. 1999. The disabled 1 phosphotyrosine-binding domain binds to the internalization signals of transmembrane glycoproteins and to phospholipids. Mol. Cell. Biol. 19: 5179–5188.
Howell, B.W., Herrick, T.M., Hildebrand, J.D., Zhang, Y., and Cooper, J.A. 2000. Dab1 tyrosine phosphorylation sites relay positional signals during mouse brain development. Curr. Biol. 10: 877–885.[CrossRef][Medline]
Hu, H., Yang, Y., Eade, A., Xiong, Y., and Qi, Y. 2007. Breaches of the pial basement membrane and disappearance of the glia limitans during development underlie the cortical lamination defect in the mouse model of muscle–eye–brain disease. J. Comp. Neurol. 501: 168–183.[CrossRef][Medline]
Kubo, K., Mikoshiba, K., and Nakajima, K. 2002. Secreted Reelin molecules form homodimers. Neurosci. Res. 43: 381–388.[CrossRef][Medline]
Kuo, G., Arnaud, L., Kronstad-O’Brien, P., and Cooper, J.A. 2005. Absence of Fyn and Src causes a reeler-like phenotype. J. Neurosci. 25: 8578–8586.
Lein, E.S., Hawrylycz, M.J., Ao, N., Ayres, M., Bensinger, A., Bernard, A., Boe, A.F., Boguski, M.S., Brockway, K.S., Byrnes, E.J., et al. 2007. Genome-wide atlas of gene expression in the adult mouse brain. Nature 445: 168–176.[CrossRef][Medline]
Levkowitz, G., Waterman, H., Ettenberg, S.A., Katz, M., Tsygankov, A.Y., Alroy, I., Lavi, S., Iwai, K., Reiss, Y., Ciechanover, A., et al. 1999. Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. Mol. Cell 4: 1029–1040.[CrossRef][Medline]
Lupher, M.L., Songyang, Z., Shoelson, S.E., Cantley, L.C., and Band, H. 1997. The Cbl phosphotyrosine-binding domain selects a D(N/D)XpY motif and binds to the Tyr292 negative regulatory phosphorylation site of ZAP-70. J. Biol. Chem. 272: 33140–33144.
Luque, J.M., Morante-Oria, J., and Fairen, A. 2003. Localization of ApoER2, VLDLR and Dab1 in radial glia: Groundwork for a new model of reelin action during cortical development. Brain Res. 140: 195–203.[CrossRef]
Meng, W., Sawasdikosol, S., Burakoff, S.J., and Eck, M.J. 1999. Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase. Nature 398: 84–90.[CrossRef][Medline]
Ogawa, M., Miyata, T., Nakajima, K., Yagyu, K., Seike, M., Ikenaka, K., Yamamoto, H., and Mikoshiba, K. 1995. The reeler gene-associated antigen on Cajal-Retzius neurons is a crucial molecule for laminar organization of cortical neurons. Neuron 14: 899–912.[CrossRef][Medline]
Park, T.J., Hamanaka, H., Ohshima, T., Watanabe, N., Mikoshiba, K., and Nukina, N. 2003. Inhibition of ubiquitin ligase Siah-1A by disabled-1. Biochem. Biophys. Res. Commun. 302: 671–678.[CrossRef][Medline]
Petroski, M.D. and Deshaies, R.J. 2005. Function and regulation of cullin–RING ubiquitin ligases. Nat. Rev. 6: 9–20.[CrossRef]
Rice, D.S., Sheldon, M., D’Arcangelo, G., Nakajima, K., Goldowitz, D., and Curran, T. 1998. Disabled-1 acts downstream of Reelin in a signaling pathway that controls laminar organization in the mammalian brain. Development 125: 3719–3729.[Abstract]
Sheldon, M., Rice, D.S., D’Arcangelo, G., Yoneshima, H., Nakajima, K., Mikoshiba, K., Howell, B.W., Cooper, J.A., Goldowitz, D., and Curran, T. 1997. Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice. Nature 389: 730–733.[CrossRef][Medline]
Strasser, V., Fasching, D., Hauser, C., Mayer, H., Bock, H.H., Hiesberger, T., Herz, J., Weeber, E.J., Sweatt, J.D., Pramatarova, A., et al. 2004. Receptor clustering is involved in Reelin signaling. Mol. Cell. Biol. 24: 1378–1386.
Suetsugu, S., Tezuka, T., Morimura, T., Hattori, M., Mikoshiba, K., Yamamoto, T., and Takenawa, T. 2004. Regulation of actin cytoskeleton by mDab1 through N-WASP and ubiquitination of mDab1. Biochem. J. 384: 1–8.[CrossRef][Medline]
Thien, C.B. and Langdon, W.Y. 2001. Cbl: Many adaptations to regulate protein tyrosine kinases. Nat. Rev. 2: 294–307.[CrossRef]
Trommsdorff, M., Borg, J.P., Margolis, B., and Herz, J. 1998. Interaction of cytosolic adaptor proteins with neuronal apolipoprotein E receptors and the amyloid precursor protein. J. Biol. Chem. 273: 33556–33560.
Trommsdorff, M., Gotthardt, M., Hiesberger, T., Shelton, J., Stockinger, W., Nimpf, J., Hammer, R.E., Richardson, J.A., and Herz, J. 1999. Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell 97: 689–701.[CrossRef][Medline]
Zaki, M., Shehab, M., El-Aleem, A.A., Abdel-Salam, G., Koeller, H.B., Ilkin, Y., Ross, M.E., Dobyns, W.B., and Gleeson, J.G. 2007. Identification of a novel recessive RELN mutation using a homozygous balanced reciprocal translocation. Am. J. Med. Genet. 143: 939–944.
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