Siah2 integrates mitogenic and extracellular matrix signals linking neuronal progenitor ciliogenesis with germinal zone occupancy

Abstract

Evidence is lacking as to how developing neurons integrate mitogenic signals with microenvironment cues to control proliferation and differentiation. We determined that the Siah2 E3 ubiquitin ligase functions in a coincidence detection circuit linking responses to the Shh mitogen and the extracellular matrix to control cerebellar granule neurons (CGN) germinal zone (GZ) occupancy. We found that Shh maintains Siah2 expression in CGN progenitors (GNPs) in a Ras/Mapk-dependent manner. Siah2 supports ciliogenesis in a feed-forward fashion by restraining ciliogenic targets. Efforts to identify GZ sources of Ras/Mapk signaling led us to discover that GNPs respond to laminin, but not vitronectin, in the microenvironment via integrin β1 receptors, which engages the Ras/Mapk cascade, and that this niche interaction is essential for promoting GNP ciliogenesis. As GNPs leave the GZ, differentiation is seamlessly driven by changing extracellular cues that diminish Siah2-activity leading to primary cilia retraction and attenuation of mitogenic responses.