Suppressor of Fused regulates the proliferation of postnatal neural stem and precursor cells via a Gli3-dependent mechanism.

Hector G Gomez,Samuel J Pleasure,Jesse Garcia Castillo,Odessa R Yabut,David Aguilar,Hirofumi Noguchi

doi:10.1242/bio.039248

Hector G Gomez, Samuel J Pleasure + Show 4 more

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https://doi.org/10.1242/bio.039248

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Journal: Biology open	Publication Date: Jan 1, 2019
Citations: 7	License type: CC BY 4.0

Affiliation: University of California, San Francisco

Abstract

ABSTRACTThe ventricular-subventricular zone (V-SVZ) of the forebrain is the source of neurogenic stem/precursor cells for adaptive and homeostatic needs throughout the life of most mammals. Here, we report that Suppressor of Fused (Sufu) plays a critical role in the establishment of the V-SVZ at early neonatal stages by controlling the proliferation of distinct subpopulations of stem/precursor cells. Conditional deletion of Sufu in radial glial progenitor cells (RGCs) at E13.5 resulted in a dramatic increase in the proliferation of Sox2+ Type B1 cells. In contrast, we found a significant decrease in Gsx2+ and a more dramatic decrease in Tbr2+ transit amplifying cells (TACs) indicating that innate differences between dorsal and ventral forebrain derived Type B1 cells influence Sufu function. However, many precursors accumulated in the dorsal V-SVZ or failed to survive, demonstrating that despite the over-proliferation of Type B1 cells, they are unable to transition into functional differentiated progenies. These defects were accompanied by reduced Gli3 expression and surprisingly, a significant downregulation of Sonic hedgehog (Shh) signaling. Therefore, these findings indicate a potential role of the Sufu-Gli3 regulatory axis in the neonatal dorsal V-SVZ independent of Shh signaling in the establishment and survival of functional stem/precursor cells in the postnatal dorsal V-SVZ.

Highlights

Tissue-specific stem cell niches persist at postnatal stages as the source of multiple cell types throughout the life of most animal species
We found that the total number of BrdU+ cells in the olfactory bulb (OB) of control and mutant mice did not significantly differ (Fig. 6H, 0.08992±0.01195 cells per 100 μm2 for n=3 controls and 0.08334±0.004048 cells per 100 μm2 for n=3 mutants; P-value=0.6297), indicating that proper numbers of immature neurons originating from the P7 hGFAP-Cre; Sufufl/fl V-SVZ migrated into the OB
Our study provides insights into the molecular mechanisms involved in the formation of a molecularly distinct neurogenic domain, the dorsal V-SVZ

Summary

Introduction

Tissue-specific stem cell niches persist at postnatal stages as the source of multiple cell types throughout the life of most animal species. In the mammalian forebrain, in rodents, the ventricular-subventricular zone (V-SVZ) lining the lateral ventricles is a prominent postnatal stem cell niche capable of generating neuronal and glial cell progenies. The adult V-SVZ is composed of Type B1 cells, transit amplifying Type C cells (TACs), Type A cells and a monolayer of. Type B1 cells are the primary neural stem cells (NSC) of the V-SVZ, capable of generating TACs that divide into immature cell types that migrate into various forebrain structures where they mature (Lim and Alvarez-Buylla, 2016). Neurogenic TACs differentiate into immature neurons or Type A cells that migrate through the rostral migratory stream (RMS) and differentiate into molecularly distinct interneuron subtypes of the OB circuitry

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