Antagonistic action of Siah2 and Pard3/JamC to promote germinal zone exit of differentiated cerebellar granule neurons by modulating Ntn1 signaling via Dcc

Summary Germinal zone (GZ) exit is at the top of a cascade of events promoting the maturation of neurons and their assembly into neuronal circuits. Developing neurons and their progenitors must interpret varied niche signals like morphogens, guidance molecules, extracellular matrix, or adhesive cues to navigate GZ occupancy. How newborn neurons integrate multiple cell-extrinsic niche cues with their cell-intrinsic machinery in exiting a GZ is unknown. We establish cooperation between cell polarity-regulated adhesion and Netrin-1 signaling comprises a coincidence detection circuit repelling maturing neurons from their GZ. In this circuit, the Partitioning defective 3 (Pard3) polarity protein and Junctional adhesion molecule-C (JAM-C) adhesion protein promote, while the Seven in absentia 2 (Siah2) ubiquitin ligase inhibits, Deleted in colorectal cancer (DCC) receptor surface recruitment to gate differentiation linked repulsion to GZ Netrin-1. These results demonstrate cell polarity as a central integrator of adhesive- and guidance cues cooperating to spur GZ exit. Highlights-Netrin1 expressed in the cerebellar GZ ranges from an attractive to repulsive cue depending on differentiation status or extracellular matrix context.-Modulation of DCC expression levels impacts the nature of the Netrin1 response and GZ occupancy status.-Siah2, Pard3, and JamC function to modulate responsiveness to purified Netrin1 and cooperate with Dcc to regulate GZ exit.-Pard3 and JamC promote both basal and Netrin1 stimulated DCC surface recruitment to control GZ exit and Netrin1 repulsion