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

Taren Ong,Sharon Frase,Randall Wakefield,Niraj Trivedi,David J Solecki

doi:10.1038/s41467-020-19063-7

Taren Ong, Sharon Frase + Show 3 more

Open Access

https://doi.org/10.1038/s41467-020-19063-7

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Abstract

Evidence is lacking as to how developing neurons integrate mitogenic signals with microenvironment cues to control proliferation and differentiation. We determine 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) GZ occupancy. We show that Shh signaling maintains Siah2 expression in CGN progenitors (GNPs) in a Ras/Mapk-dependent manner. Siah2 supports ciliogenesis in a feed-forward fashion by restraining cilium disassembly. Efforts to identify sources of the Ras/Mapk signaling led us to discover that GNPs respond to laminin, but not vitronectin, in the GZ microenvironment via integrin β1 receptors, which engages the Ras/Mapk cascade with Shh, and that this niche interaction is essential for promoting GNP ciliogenesis. As GNPs leave the GZ, differentiation is driven by changing extracellular cues that diminish Siah2-activity leading to primary cilia shortening and attenuation of the mitogenic response.

Highlights

Evidence is lacking as to how developing neurons integrate mitogenic signals with microenvironment cues to control proliferation and differentiation
Intrigued by the reported connection between the Ras/Map kinase (MAPK) signaling pathway and Siah E3 ubiquitin ligases[22,23,24], we were curious as to whether this relationship was conserved in Granule neuron progenitors (GNPs) neurogenesis and germinal zone (GZ) exit
Previous results have shown that Siah[2] restrains radial migration in progenitors by tagging for ubiquitin-proteasome degradation targets that are required for the pro-migratory adhesive interactions via Pard[3] and actin–microtubule crosslinking via Dbn that are essential for GZ exit and migration along glial fibers[16,20]

Summary

Introduction

Evidence is lacking as to how developing neurons integrate mitogenic signals with microenvironment cues to control proliferation and differentiation. We determine that the Siah[2] 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) GZ occupancy. As Pard[3] and Dbn act in CGNs to promote radial migration, the relief of Siah2-target inhibition in neuronal differentiation represents a form of integration for cell biological activities linked to GZ exit, positioning Siah[2] as a mechanistic entry point through which to explore how GNPs maintain position in their germinal niche. We uncover a surprising link between mitogen signaling and the CGN GZ-exit machinery, as Shh signaling maintains Siah[2] expression in proliferative GNPs. We show that the perduring EGL that results from deregulated Shh signaling in GNPs can be rescued by blocking Ras/MAPK and Siah[2]. Siah[2] is central to this model because GNPs employ this ubiquitin ligase to maintain GZ occupancy and sensitivity to Shh signaling in a process that is integrated with the engagement of ECM components in their niche

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