Grimaldi Piercesare, Parras Carlos, Guillemot François, Rossi Ferdinando, Wassef Marion
CNRS UMR 8542, Biology Department, Ecole Normale Supérieure, 46 Rue d'Ulm, 75005 Paris, France.
Dev Biol. 2009 Apr 15;328(2):422-33. doi: 10.1016/j.ydbio.2009.02.008. Epub 2009 Feb 13.
Cerebellar GABAergic interneurons and glia originate from progenitors that delaminate from the ventricular neuroepithelium and proliferate in the prospective white matter. Even though this population of progenitor cells is multipotent as a whole, clonal analysis indicates that different lineages are already separated during postnatal development and little is known about the mechanisms that regulate the specification and differentiation of these cerebellar types at earlier stages. Here, we investigate the role of Ascl1 in the development of inhibitory interneurons and glial cells in the cerebellum. This gene is expressed by maturing oligodendrocytes and GABAergic interneurons and is required for the production of appropriate quantities of these cells, which are severely reduced in Ascl1(-/-) mouse cerebella. Nevertheless, the two lineages are not related and the majority of oligodendrocytes populating the developing cerebellum actually derive from extracerebellar sources. Targeted electroporation of Ascl1-expression vectors to ventricular neuroepithelium progenitors enhances the production of interneurons and completely suppresses astrocytic differentiation, whereas loss of Ascl1 function has opposite effects on both cell types. Our results indicate that Ascl1 directs ventricular neuroepithelium progenitors towards inhibitory interneuron fate and restricts their ability to differentiate along the astroglial lineage.
小脑γ-氨基丁酸能中间神经元和神经胶质细胞起源于从脑室神经上皮层脱离并在前瞻性白质中增殖的祖细胞。尽管这群祖细胞总体上具有多能性，但克隆分析表明，不同的谱系在出生后发育过程中就已经分离，而对于在早期阶段调节这些小脑细胞类型的特化和分化的机制，我们知之甚少。在这里，我们研究了Ascl1在小脑抑制性中间神经元和神经胶质细胞发育中的作用。该基因在成熟的少突胶质细胞和γ-氨基丁酸能中间神经元中表达，并且是产生适量这些细胞所必需的，在Ascl1基因敲除小鼠的小脑中，这些细胞数量严重减少。然而，这两个谱系并无关联，发育中小脑中的大多数少突胶质细胞实际上来源于小脑外的来源。将Ascl1表达载体靶向电穿孔到脑室神经上皮祖细胞中可增强中间神经元的产生，并完全抑制星形胶质细胞的分化，而Ascl1功能丧失对这两种细胞类型都有相反的影响。我们的结果表明，Ascl1引导脑室神经上皮祖细胞走向抑制性中间神经元命运，并限制它们沿星形胶质细胞谱系分化的能力。
