Gomez Hector G, Noguchi Hirofumi, Castillo Jesse Garcia, Aguilar David, Pleasure Samuel J, Yabut Odessa R
Department of Neurology.
Department of Neurology
Biol Open. 2019 Jun 6;8(6):bio039248. doi: 10.1242/bio.039248.
The 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.
前脑的脑室下区（V-SVZ）是大多数哺乳动物一生中适应性和稳态需求的神经源性干细胞/前体细胞的来源。在此，我们报告，融合抑制因子（Sufu）在新生儿早期阶段通过控制不同亚群的干细胞/前体细胞的增殖，在V-SVZ的建立中发挥关键作用。在E13.5时，在放射状胶质祖细胞（RGCs）中条件性删除Sufu导致Sox2+ B1型细胞的增殖显著增加。相反，我们发现Gsx2+细胞显著减少，而Tbr2+过渡放大细胞（TACs）减少更为显著，这表明背侧和腹侧前脑来源的B1型细胞之间的固有差异影响Sufu功能。然而，许多前体细胞积聚在背侧V-SVZ或未能存活，这表明尽管B1型细胞过度增殖，但它们无法转变为功能性分化后代。这些缺陷伴随着Gli3表达的降低，令人惊讶的是，还伴随着音猬因子（Shh）信号的显著下调。因此，这些发现表明Sufu-Gli3调节轴在新生儿背侧V-SVZ中具有潜在作用，在出生后背侧V-SVZ功能性干细胞/前体细胞的建立和存活中独立于Shh信号。
