Laboratory of Stem Cell Biology and Developmental Genetics, The Francis Crick Institute, London, UK.
UK Dementia Research Institute, Imperial College London, London, UK.
Dev Neurobiol. 2022 Oct;82(7-8):565-580. doi: 10.1002/dneu.22899. Epub 2022 Sep 20.
The adult dentate gyrus (DG) of rodents hosts a neural stem cell (NSC) niche capable of generating new neurons throughout life. The embryonic origin and molecular mechanisms underlying formation of DG NSCs are still being investigated. We performed a bulk transcriptomic analysis on mouse developing archicortex conditionally deleted for Sox9, a SoxE transcription factor controlling both gliogenesis and NSC formation, and identified Hopx, a recently identified marker of both prospective adult DG NSCs and astrocytic progenitors, as being downregulated. We confirm SOX9 is required for HOPX expression in the embryonic archicortex. In particular, we found that both NSC markers are highly expressed in the cortical hem (CH), while only weakly in the adjacent dentate neuroepithelium (DNE), suggesting a potential CH embryonic origin for DG NSCs. However, we demonstrate both in vitro and in vivo that the embryonic CH, as well as its adult derivatives, lacks stem cell potential. Instead, deletion of Sox9 in the DNE affects both HOPX expression and NSC formation in the adult DG. We conclude that HOPX expression in the CH is involved in astrocytic differentiation downstream of SOX9, which we previously showed regulates DG development by inducing formation of a CH-derived astrocytic scaffold. Altogether, these results suggest that both proteins work in a dose-dependent manner to drive either astrocytic differentiation in CH or NSC formation in DNE.
成年啮齿动物的齿状回（DG）拥有一个神经干细胞（NSC）龛位，能够在整个生命过程中产生新的神经元。DG NSCs 的胚胎起源和分子机制仍在研究中。我们对条件性敲除 Sox9 的发育中的鼠弓状皮质进行了批量转录组分析，Sox9 是一种 SoxE 转录因子，控制着神经胶质发生和 NSC 形成，我们发现 Hopx，一种新鉴定的成年 DG NSCs 和星形胶质祖细胞的标志物，表达下调。我们证实 SOX9 是胚胎弓状皮质中 HOPX 表达所必需的。特别是，我们发现两种 NSC 标志物在皮质半球（CH）中高度表达，而在相邻的齿状神经上皮（DNE）中表达较弱，这表明 DG NSCs 可能来源于 CH 胚胎。然而，我们在体外和体内证明，胚胎 CH 及其成年衍生物缺乏干细胞潜能。相反，DNE 中 Sox9 的缺失会影响成年 DG 中 HOPX 的表达和 NSC 的形成。我们得出结论，CH 中的 HOPX 表达参与了 SOX9 下游的星形胶质细胞分化，我们之前的研究表明，SOX9 通过诱导 CH 衍生的星形胶质细胞支架的形成来调节 DG 的发育。总之，这些结果表明，这两种蛋白以剂量依赖的方式共同作用，要么在 CH 中促进星形胶质细胞分化，要么在 DNE 中促进 NSC 形成。
