DSCAM regulates delamination of neurons in the developing midbrain.

Abstract

For normal neurogenesis and circuit formation, delamination of differentiating neurons from the proliferative zone must be precisely controlled; however, the regulatory mechanisms underlying cell attachment are poorly understood. Here, we show that Down syndrome cell adhesion molecule (DSCAM) controls neuronal delamination by local suppression of the RapGEF2-Rap1-N-cadherin cascade at the apical endfeet in the dorsal midbrain. <i>Dscam</i> transcripts were expressed in differentiating neurons, and DSCAM protein accumulated at the distal part of the apical endfeet. Cre-<i>loxP</i>-based neuronal labeling revealed that <i>Dscam</i> knockdown impaired endfeet detachment from ventricles. DSCAM associated with RapGEF2 to inactivate Rap1, whose activity is required for membrane localization of N-cadherin. Correspondingly, <i>Dscam</i> knockdown increased N-cadherin localization and ventricular attachment area at the endfeet. Furthermore, excessive endfeet attachment by <i>Dscam</i> knockdown was restored by co-knockdown of <i>RapGEF2</i> or <i>N-cadherin</i> Our findings shed light on the molecular mechanism that regulates a critical step in early neuronal development.