SARA regulates neuronal migration during neocortical development through L1 trafficking

Abstract

Emerging evidence suggests that endocytic trafficking of adhesion proteins plays a crucial role in neuronal migration during neocortical development. However, molecular insights into these processes remain elusive. Here, we study the early endosomal protein Smad anchor for receptor activation (SARA) in the developing mouse brain. SARA is enriched at the apical endfeet of radial glia of the neocortex. Although SARA knockdown did not lead to detectable neurogenic phenotypes, SARA-suppressed neurons exhibited impaired orientation and migration across the intermediate zone. Mechanistically, we show that SARA knockdown neurons exhibit increased surface expression of the L1 cell adhesion molecule. Neurons ectopically expressing L1 phenocopy the migration and orientation defects caused by SARA knockdown and display increased contact with neighboring neurites. L1 knockdown effectively rescues SARA suppressioninduced phenotypes. SARA knockdown neurons eventually overcome their migration defect and enter later into the cortical plate. Nevertheless, these neurons localize at more superficial cortical layers than their control counterparts. These results suggest that SARA regulates the orientation, multipolar-to-bipolar transition and the positioning of cortical neurons via modulating surface L1 expression.

Tuba activates Cdc42 during neuronal polarization downstream of the small GTPase Rab8a

“…IUE were carried out following previous reports (Fuentes et al, 2012;Mestres et al, 2016). Briefly, pregnant E15.5 C57BL/6 mice were anesthetized with isofluorane/oxygen mix (4% for induction and 2% for maintenance) during the whole surgery, and Tramadol (5 mg/Kg) was used as analgesia during the procedure.…”

Nervous system development relies on endosomal trafficking

“…13,[18][19][20] Acute knockdown of SARA expression in the developing neocortex does not crucially affect the progenitor asymmetric division nor cell fate choice of daughter cells. 17 Accordingly, SARA knockout mouse brains develop to normal size (unpublished).…”

“…27 In turn, the mislocalization of N-cadherin leads to migration arrest of postmitotic neurons in the intermediate zone (IZ) of the brain cortex. Similarly, interference with dynamin increases the Neuronal horizontal orientation and migration delay [17] accumulation of b1-integrin and focal adhesion kinase at the cell rear, and hence inhibits cell detachment and movement. 23 Moreover, Rab7-dependent lysosomal degradation (of N-cadherin and perhaps other adhesion components) is important for the final phase of somal translocation and dendrite morphogenesis.…”

“…29 We and others showed that either up-or down-regulating the expression level of L1 in cortical neurons disrupts their radial migration. 17,30 Mutations in the L1 gene have been linked to hydrocephalus in several human congenital brain disorders. 29,31 While in vitro studies have shown that the axonal plasma membrane distribution of L1 is regulated by a transcytotic pathway, 32,33 how the surface expression of L1 is regulated in migrating neurons was unknown until recently.…”

“…We also found that SARA-silenced neurons with increased surface L1 preferably bind to their neighboring neurons instead of radial glial cells, as control neurons do. 17 In all, a handful of papers have provided the first pieces of evidence about how the endosomal system coordinates different aspects of nervous system development. Even though differential sorting has been implicated in asymmetric mitosis, it seems highly context-dependent.…”