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PERSPECTIVE

A missed exit: sets in motion Dab1 polyubiquitination to put the break on neuronal migration

Ge´raldine Kerjan and Joseph G. Gleeson1 Neurogenetics Laboratory, Department of Neurosciences, University of California at San Diego, La Jolla, California 92093, USA

In 1951, Douglas Scott Falconer first described the The binding of Reelin to its receptors induces the tyro- spontaneous mutant mouse (Falconer 1951). In those sine phosphorylation of the cytoplasmic adaptor mice, cortical neurons are generated normally but mi- Dab1, which interacts with the conserved motif NPxY in grate abnormally, resulting in an inversion of the cortical the cytoplasmic tails of VLDLR and ApoER2 (Tromms- laminar organization, with later-born neurons remaining dorff et al. 1998; Howell et al. 1999). in the deeper layers of the cortex. Forty-four years later, In addition, Dab1 binds to and is phophorylated by D’Arcangelo et al. (1995) identified the causative nonreceptor tyrosine kinases from the Src family (SFK): Rln and the encoded protein Reelin. Reelin pathway mu- Src and Fyn (Arnaud et al. 2003a; Kuo et al. 2005). No- tants, and particularly mice with of its intra- ticeably, the mouse Dab1 was originally identified in a cellular effector Dab1 (Disabled-1), probably represent yeast two-hybrid screen for Src-interacting the most-studied phenotype of altered neuronal migra- (Howell et al. 1997). Src and Fyn are activated (phos- tion. The observations that mutations of Dab1 pheno- phorylated) through the Reelin pathway, and thus to- copy the Rln , and that Dab1 is up-regulated in gether, Dab1 tyrosine phosphorylation and SFK phos- reeler mice suggested the existence of a negative feed- phorylation are two interdependent mechanisms that are back loop in Reelin signaling via the regulation of Dab1 part of a positive feedback loop (Arnaud et al. 2003b; levels. In the previous issue of & Development, Bock and Herz 2003). Feng et al. (2007) presented the first coherent model to In the developing cortex, Reelin is specifically ex- explain the mechanism of Reelin-mediated Dab1 down- pressed by horizontally orientated Cajal-Retzius neurons regulation. They proposed that Reelin both activates and located in the preplate before its splitting and then in the down-regulates its effector Dab1, first by inducing its outermost layer of the cortex (the marginal zone of the phosphorylation, which then causes its targeting by an developing brain, becoming layer I of the mature brain) E3 ligase complex (EBC) containing SOCS fam- (Fig. 1; D’Arcangelo et al. 1995; Ogawa et al. 1995). On ily proteins and Cullin5 (Cul5). The impairment of this the other hand, ApoER2, VLDLR, and Dab1 are ex- down-regulation mechanism in vivo leads to a unique pressed by both cortical neurons and radial cells sup- phenotype in the cortex where neurons migrate past porting their migration (Forster et al. 2002; Frotscher et their target layer. al. 2003; Hartfuss et al. 2003; Luque et al. 2003). Strik- ingly, mutations of both VLDLR and ApoER2,ofDab1 and particularly point mutations at five Dab1 tyrosine The known side of Reelin/Dab1 signaling phosphorylation sites (Dab15F mutation of Tyr185, Reelin is a large matrix-associated transmembrane gly- Tyr198, Tyr200, Tyr220, and Tyr232), or mutation of Src Fyn reeler coprotein expressed by specific neuronal populations both SFK and result in a phenocopy of the throughout the developing CNS. Reelin has been shown phenotype, with a failure to split the preplate as well as to homodimerize, at least in vitro, and to bind to and inverting cortical layering (Howell et al. 1997, 2000; cluster two receptors from the LDL (low-density lipopro- Sheldon et al. 1997; Benhayon et al. 2003; Kuo et al. tein) family: VLDLR (very low-density lipoprotein recep- 2005), validating that they participate in a common sig- tor) and ApoER2 ( E type2) naling pathway regulating cortical neuronal migration. (D’Arcangelo et al. 1999; Hiesberger et al. 1999; Trom- msdorff et al. 1999; Kubo et al. 2002; Strasser et al. 2004). Down-regulating Dab1 Desensitization is a key feature of most signaling path- ways as it allows a system to reset and thus regain sen- 1Corresponding author. E-MAIL [email protected]; FAX (858) 534-1437. sitivity to repeated stimulation. Many studies demon- Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1622907. strated that the Reelin pathway displays such a negative

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Dab1 processing

Figure 1. Proposed model of Dab1 down-regulation during cortical neuron migration. During cortical development, neurons (green) migrate along radial glia processes (light gray) from the ventricular zone (VZ) (where they are generated) to their final position within the cortical plate (CP). Later-born neurons (progressively darker green shade) bypass previously deposited neuronal (i.e., earlier-born) neurons (lighter green), thus organizing the cortex in an “inside-out” manner. Reelin is secreted by Cajal-Retzius cells (red) located at early developmental stages (i) within the preplate (PP) before it splits into the subplate (SP) and the marginal zone (MZ), and at later stages (ii) within the marginal zone. Both neurons and radial glia cells express Reelin receptors VLDLR and ApoER2 (orange) and are responsive to Reelin. Reelin signaling displays a negative feedback regulation by which Reelin limits its own action by down- regulating the level of its effector Dab1. Feng et al. (2007) demonstrated that reelin-induced phosphorylation of Dab1 on Tyr185 and Tyr198 cause the polyubiquitination of Dab1 (Ub) by E3 ubiquitin ligases containing SOCS proteins and Cul5. Polyubiquitinated Dab1 is then degraded by the proteasome. Correct cortical development requires a strictly regulated balance of Reelin signaling and its negative feedback. During neuronal migration through the deeper layers of the cortex (a), Dab1 level is normally low (light yellow), potentially due to its distance to the Reelin source at this time, or to its down-regulation induced by Reelin encountered at an early stage of development (i). (b) The uninhibited Dab1 signaling (bright yellow) may be required for the neuron to progress through previously deposited neuronal layers. (c) In turn, Dab1 down-regulation may be necessary to stop neuron movement and avoid “overmigration.” (SVZ) Subventricular zone; (IZ) intermediate zone. feedback mechanism. It has been shown that the disrup- tical neuron culture system. Tyr198 had been formerly tion of Reelin signaling (by genetic disruption of Reelin, predicted as a potential Reelin-induced Dab1 phosphory- VLDLR, ApoER2,orFyn and Src) leads to the accumu- lation site by a Web-based PESTfind algorithm; however, lation of Dab1 protein in vivo, suggesting that Reelin the same method failed to identify Tyr185, but instead limits its action in responsive neurons by eventually predicted the importance of Tyr220 (Bock et al. 2004). down-regulating Dab1 levels (Sheldon et al. 1997; Rice et Among the potential complexes target- al. 1998; Trommsdorff et al. 1999; Arnaud et al. 2003b; ing Dab1 in the presence of Reelin, the E3 ligase Cbl Bock and Herz 2003; Kuo et al. 2005). Interestingly, this seemed a good candidate to mediate Dab1 degradation. Dab1 down-regulation happens post-transcriptionaly, as Indeed, Cbl is abundantly expressed in cortical neurons Dab1 mRNA expression is unchanged in the deficient and contains a phospho-tyrosine recognition domain cells (Rice et al. 1998). Several recent advances provide comprising an EF-hand and a SH2-like structure through further understanding of the mechanism of this post- which it binds phospho-tyrosine residues, followed by a transcriptional down-regulation of Dab1. Arnaud et al. hydrophobic residue at pY + 4 (fourth residue after the (2003a) and Bock et al. (2004) previously showed in pri- phospho-tyrosine). These are similar to the motifs found mary neuronal cultures that Dab1 is down-regulated at phosphorylation sites Tyr185 and Tyr198 of Dab1 through polyubiquitination and targeting to the protea- (Lupher et al. 1997; Meng et al. 1999). Previous studies some in the presence of Reelin, and that this modifica- showed that Cbl can ubiquitinate Dab1, at least in trans- tion requires tyrosine phosphorylation of Dab1. More- fected COS7 cells (Suetsugu et al. 2004). However, Arnaud over, inhibition of Dab1 tyrosine phosphorylation and et al. (2003a) failed to detect complexed Cbl and Dab1 by inhibition of SFK activation blocks Dab1 down-regula- immunoprecipitation, or tyrosine-phosphorylated Cbl tion (Arnaud et al. 2003b; Bock et al. 2004; Kuo et al. in Reelin-stimulated primary neuron cultures, which are 2005). Feng et al. (2007) identified two critical Dab1 ty- required for its activation as an E3 ligases (Levkowitz et rosine phosphorylation sites (primary Tyr198, and also al. 1999). Additionally, targeted deletion of Cbl in mice Tyr185), both at YQxI sequences, essential for the Dab1 failed to induce neurodevelopmental defects reminiscent degradation in response to Reelin, in an embryonic cor- of the reeler phenotype (Thien and Langdon 2001).

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Kerjan and Gleeson

Feng et al. (2007) identifed another type of EBC poten- endfeet (Hu et al. 2007). Interestingly, Cul5 knockdown tially regulating Dab1 in vivo. They also used non- neurons remain at the surface of the cortex, instead of be- neuronal cells lines such as COS7, in which Dab1, when ing bypassed by younger neurons. This defect is partially coexpressed with Fyn and Src, is known to be constitu- rescued in vivo by the coelectroporation of Dab1 short tively tyrosine phophorylated but not degraded. This hairpin RNA (shRNA). Furthermore Cul5 shRNA stops suggests that a component of the degradation machinery Dab1 degradation in vitro, validating that the overmigra- targeting phospho-tyrosine Dab1 is absent or limiting in tion is due to the inhibition of Dab1 degradation. this in vitro system, which thus makes it particularly In the developing cortex, neurons migrate along the adapted for a candidate approach. Feng et al. (2007) tested processes of their parental radial glia from the ventricu- several E3 ubiquitin ligases in this nonneuronal cell sys- lar zone to the more superficial cortical layer and stop tem and show that the SOCS1–3 ligases can bind to when they reach the marginal zone. Later-born neurons Dab1, and induce Tyr185 or Tyr198 phophorylated Dab1 migrate through previously deposited neurons in cortical degradation, in a Fyn-dependent manner. Interestingly, plate, leading to an inside-out lamination of the cortex they also tested Cbl in this assay and show that it fails to (Fig. 1). The reeler phenotype displayed by Rln-deficient induce Dab1 degradation, further invalidating the Cbl mice as well as mice deficient for VLDLR and ApoER2, implication hypothesis. Because many SOCS proteins Dab1, and Src and Fyn mutant show a rough inversion of are expressed during brain development (among them the normal inside-out pattern of cortical migration and SOCS1–3) and might be functionally redundant, Feng et an excess of neurons in the normally cell-sparse mar- al. (2007) chose to study the consequence of the inacti- ginal zone (Caviness and Sidman 1973; Howell et al. vation of another component of the SOCS-containing 1997, 2000; Sheldon et al. 1997; Benhayon et al. 2003; EBC on Reelin-induced degradation of Dab1: the cullin Kuo et al. 2005). The commonly accepted explanation for Cul5 (Petroski and Deshaies 2005). Cul5 recently has this phenotype is that the newly arrived neurons fail to been shown and confirmed in the study by Feng et al. penetrate the preplate and split it appropriately into the (2007) to be expressed in mouse cortical neurons (Lein et marginal zone and subplate, and cannot bypass previ- al. 2007), but its role was so far completely unknown. ously deposited neurons and accumulate in an outside-in Feng et al. (2007) showed that in cultured cortical neu- manner. Dab1 seems necessary to achieve the bypassing rons, Cul5 binds to Dab1, and that Cul5 knockdown spe- step in mosaic Dab1 wt; Dab1−/− embryos, mutant neu- cifically protects Dab1 from Reelin-induced degradation. rons lie below wild-type neurons (Hammond et al. 2001), Noticeably, Dab1 interaction with ubiquitin ligases may and BrdU pulse-labeling experiments showed that Dab1 also have other biological significance. Dab1 has been knockdown neurons accumulate in deep cortical plate shown to interact with the E3 ubiquitin ligase Siah-1A in and fail to pass their earlier-born siblings. Furthermore, yeast two-hybrid assays and coimmunoprecipitation ex- neurons showing an abnormally high level of Dab1 mi- periments in 293T cells. But in that case, Dab1–Siah1 grate presumably faster through the cortical plate and binding induces the inhibition of Siah-1A ubiquitinating stick to the marginal zone, preventing the passage of activity (Park et al. 2003). Thus, one might wonder if their siblings (Feng et al. 2007). Dab1 could additionally regulate EBC containing SOCS Overall, those results strongly suggest that Dab1 is and Cul5 as well, adding a step to the complexity of this necessary for neurons to cross previously deposited neu- Reelin feedback loop. ronal layers, and in turn, Dab1 should be down-regulated in neurons to properly terminate their migration and al- low their siblings to bypass them. According to this hy- Overmigration: when Dab1 down-regulation fails pothesis, a precise regulation of Dab1 levels should be to occur required to control the precise location of the migration Feng et al. (2007) showed for the first time the in vivo arrest. A threshold response to a gradient of a signaling consequences of a failure of Dab1 down-regulation on neu- molecule may be an efficient way to control a timely ronal migration. Bock et al. (2004) showed that blocking stop. However, maintaining a Reelin gradient within the proteasome activity disturbs the proper organization of a cortical plate may be difficult as the depth and the lay- cultured embryonic cortical plate, suggesting very indi- ered organization of the cortical plate are continuously rectly that Dab1 degradation is important for its role in changing. A transcriptional mode of regulation implies regulating neuronal migration. In this paper, Feng et al. latency of protein synthesis, which is slow in the case of (2007) observed that Cul5 knockdown in the cortex leads Dab1, and of the protein half-life (12 h for Dab1) (Arnaud to an increased Dab1 level in vivo and to a unique migra- et al. 2003a), and thus is probably not an appropriate way tion defect. Cul5 knockdown neurons are located more to control a timely switch mechanism. Controlling ex- superficially within the cortical plate relative to control pression level by regulating the degradation of a con- neurons, and partly intrude into the marginal zone. This stantly synthesized protein, in a continuously respond- is the first description of such a phenotype of “over- ing neuron can constitute a very efficient method, in migration” that clearly differs from the similarly named contrast. In migrating cortical neurons, Dab1 is con- phenotype of POMGnT1 (O-mannose ␤31,2-N-acetyl- stantly down-regulated (as implied by the fact that in glucosaminyl-transferase 1)-deficient mice, in which corti- reeler mice, the Dab1 level is increased throughout the cal neurons overmigrate past the neural boundary through depth of the cortex) (Arnaud et al. 2003a) via the Cul5/ breaches in the pia matter caused by overgrown radial glial SOCS-containing E3 ligase complex. Dab1 regulation

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A missed exit: Reelin sets in motion Dab1 polyubiquitination to put the break on neuronal migration

Géraldine Kerjan and Joseph G. Gleeson

Genes Dev. 2007, 21: Access the most recent version at doi:10.1101/gad.1622907

Related Content Cullin 5 regulates Dab1 protein levels and neuron positioning during cortical development Libing Feng, Nathaniel S. Allen, Sergi Simo, et al. Genes Dev. November , 2007 21: 2717-2730

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