Neuronal progenitors in the developing forebrain undergo dynamic competence states to ensure timely generation of specific excitatory and inhibitory neuronal subtypes from distinct neurogenic niches of the dorsal and ventral forebrain, respectively. Here we show evidence of progenitor plasticity when Sonic hedgehog (SHH) signaling is left unmodulated in the embryonic neocortex of the mammalian dorsal forebrain. We found that, at early stages of corticogenesis, loss of Suppressor of Fused (Sufu), a potent inhibitor of SHH signaling, in neocortical progenitors, altered the transcriptomic landscape of male mouse embryos. Ectopic activation of SHH signaling occurred, via degradation of Gli3R, resulting in significant upregulation of fibroblast growth factor 15 (FGF15) gene expression in all E12.5 Sufu-cKO neocortex regardless of sex. Consequently, activation of FGF signaling, and its downstream effector the MAPK signaling, facilitated expression of genes characteristic of ventral forebrain progenitors. Our studies identify the importance of modulating extrinsic niche signals such as SHH and FGF15, to maintain the competency and specification program of neocortical progenitors throughout corticogenesis.

SIGNIFICANCE STATEMENT Low levels of FGF15 control progenitor proliferation and differentiation during neocortical development, but little is known on how FGF15 expression is maintained. Our studies identified SHH signaling as a critical activator of FGF15 expression during corticogenesis. We found that Sufu, via Gli3R, ensured low levels of FGF15 was expressed to prevent abnormal specification of neocortical progenitors. These studies advance our knowledge on the molecular mechanisms guiding the generation of specific neocortical neuronal lineages, their implications in neurodevelopmental diseases, and may guide future studies on how progenitor cells may be used for brain repair.

发展中的前脑中的神经元祖细胞会经历动态能力状态，以确保分别从背侧和腹侧前脑的不同神经源壁timely适时生成特定的兴奋性和抑制性神经元亚型。在这里，我们显示了当声波刺猬（SHH）信号在哺乳动物前脑的胚胎新皮层中未受到调节时祖细胞可塑性的证据。我们发现，在皮质发生的早期阶段，新皮层祖细胞中融合蛋白抑制因子（Sufu）（SHH信号的强效抑制剂）的丧失改变了雄性小鼠胚胎的转录组构象。SHH信号的异位激活通过Gli3R的降解而发生，导致成纤维细胞生长因子15（FGF15）基因在所有E12.5 Sufu-cKO新皮质中的表达，无论性别如何。因此，FGF信号传导及其下游效应器MAPK信号传导的激活促进了腹侧前脑祖细胞的特征基因的表达。我们的研究发现调节外源性利基信号（如SHH和FGF15）对于维持整个皮质发生过程中新皮质祖细胞的能力和规格程序的重要性。

重要声明在新皮质发育过程中，低水平的FGF15控制着祖细胞的增殖和分化，但是关于如何维持FGF15的表达知之甚少。我们的研究确定SHH信号传导是皮质发生过程中FGF15表达的关键激活因子。我们发现Sufu通过Gli3R确保表达低水平的FGF15，以防止新皮层祖细胞异常。这些研究提高了我们对指导特定新皮层神经元谱系生成及其在神经发育疾病中的意义的分子机制的认识，并可能指导有关祖细胞如何用于脑修复的未来研究。