Rbx2 Regulates Neuronal Migration through Different Cullin 5-RING Ligase Adaptors

Abstract

Morphogenesis requires the proper migration and positioning of different cell types in the embryo. Much more is known about how cells start and guide their migrations than how they stop when they reach their destinations. Here we provide evidence that Rbx2, a subunit of the Cullin5-RING E3 ubiquitin ligase (CRL5) complex, stops neocortical projection neurons at their target layers. Rbx2 mutation causes neocortical and cerebellar ectopias dependent on Dab1, a key signaling protein in the Reelin pathway. SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SOCS7 is up-regulated during projection neuron migration and unscheduled SOCS7 expression stops migration prematurely. Cerebellar development requires Rbx2 but not SOCS7, pointing to the importance of other CRL5 adaptors. Our results suggest that CRL5 adaptor expression is spatio-temporally regulated to modulate Reelin signaling and ensure normal neuron positioning in the developing brain.

Speed control for neuronal migration in the postnatal brain by Gmip-mediated local inactivation of RhoA

“…Consistent with this, we found that Gmip KD increased both the frequency of saltatory movements, by shortening the pause duration, and the stride length, both of which led to an increase in the speed of neuronal migration from the V-SVZ to OB. Similar regulatory mechanisms may also affect neuronal migration in other brain regions, such as the Cullin-5-mediated saltatory movement of radially migrating pyramidal neurons 7,8 . Thus, our findings suggest that the speed of neuronal migration can be precisely controlled by Gmip-mediated modulation of the stride frequency and length in the saltatory movement of the soma.…”

Cleavage within Reelin Repeat 3 Regulates the Duration and Range of the Signaling Activity of Reelin Protein

“…Reelin induces tyrosine phosphorylation of Dab1 through ApoER2/VLDLR (26,27,33,34), and phosphorylated Dab1 is quickly degraded by the ubiquitin-proteasome system (37)(38)(39)(40). Dab1 degradation is critical for the termination of neuronal migration (39).…”

“…Phosphorylated Dab1 is quickly degraded in the cytoplasm (37)(38)(39)(40), and, thus, the amount of Dab1 reflects the extent of Reelin signaling (26,33,37,40). If N-t cleavage is the major inactivation mechanism for Reelin, the duration of Reelin-PD activity should exceed that of Reelin-WT.…”

“…We showed previously that N-t cleavage virtually abolishes the ability of Reelin to induce Dab1 phosphorylation (10). Phosphorylated Dab1 is quickly degraded in the cytoplasm in a proteasome-dependent manner (37)(38)(39)(40), and the amount of Dab1 has been utilized as one of the indications of Reelin signaling (26,33,37,40). N-t cleavage is catalyzed by an unidentified metalloprotease(s) that bind(s) heparin (10).…”

Cell Regulation by Phosphotyrosine-Targeted Ubiquitin Ligases

“…Systemic SOCS7 deletion can also increase insulin sensitivity by stabilizing IRS proteins, which mediate insulin signaling, in pancreatic ␤ cells (127). Conditional knockout of SOCS7 in neural progenitors during brain development altered the migration of specific classes of neurons, consistent with hyper-responsiveness to reelin, a migration-stimulatory factor (128). SOCS7 binds to Dab1, a protein that is phosphorylated at tyrosine in reelin-stimulated neurons, and stimulates ubiquitination of pY-Dab1 in vitro.…”