The formation of the vertebrate nervous system depends on the complex interplay of morphogen signaling pathways and cell cycle progression to establish distinct cell fates. The Sonic hedgehog (Shh) signaling pathway is well understood to promote ventral cell fates in the developing spinal cord. A key regulator of Shh signaling is its receptor Patched1 (Ptch1). However, because the Ptch1 null mutation is lethal early in mouse embryogenesis, its role in controlling cell cycle progression, neurogenesis, and axon guidance in the developing spinal cord is not fully understood. An allele of Ptch1 called Wiggable (Ptch1Wig), which was previously shown to enhance Shh signaling, was used to test its ability to regulate neurogenesis and proliferation in the developing spinal cord. Ptch1Wig/Wig mutants displayed enhanced ventral proneural gene activation, and aberrant proliferation of the neural tube and floor plate cells, the latter normally being a quiescent population. The expression of the cell cycle regulators p27Kip1 and p57Kip2 were expanded in Ptch1Wig/Wig mutant spinal cords, as was the number of mitotic and S-phase nuclei, suggesting enhanced cell cycle progression. However, Ptch1Wig/Wig mutants also showed enhanced apoptosis in the ventral embryonic spinal cord, which resulted in thinner spinal cords at later embryonic stages. Commissural axons largely failed to cross the floor plate of Ptch1Wig/Wig mutant embryos, suggesting enhanced Shh signaling in these mutants led to a dorsal expansion of the chemoattraction front. These findings are consistent with a role of Ptch1 in regulating neurogenesis and proliferation of neural progenitors, and in restricting the influence of Shh signaling in commissural axon guidance to the floor plate.

中文翻译：

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Hedgehog 受体 Patched1 调节胚胎脊髓中的增殖、神经发生和轴突导向

脊椎动物神经系统的形成取决于形态原信号通路和细胞周期进程的复杂相互作用，以建立不同的细胞命运。众所周知，声波刺猬 (Shh) 信号通路可促进发育中的脊髓中的腹侧细胞命运。Shh 信号传导的一个关键调节因子是其受体 Patched1 (Ptch1)。然而，由于 Ptch1 无效突变在小鼠胚胎发生的早期是致命的，它在控制发育中的脊髓中的细胞周期进程、神经发生和轴突引导方面的作用尚不完全清楚。Ptch1 的一个称为 Wiggable (Ptch1Wig) 的等位基因以前被证明可以增强 Shh 信号，用于测试其在发育中的脊髓中调节神经发生和增殖的能力。Ptch1Wig/Wig 突变体表现出增强的腹侧前神经基因激活，以及神经管和底板细胞的异常增殖，后者通常是静止的。细胞周期调节因子 p27Kip1 和 p57Kip2 的表达在 Ptch1Wig/Wig 突变脊髓中增加，有丝分裂和 S 期细胞核的数量也增加，表明细胞周期进程增强。然而，Ptch1Wig/Wig 突变体在腹侧胚胎脊髓中也显示出增强的细胞凋亡，这导致在后期胚胎阶段脊髓变细。连合轴突在很大程度上未能穿过 Ptch1Wig/Wig 突变体胚胎的底板，这表明这些突变体中增强的 Shh 信号导致化学吸引力前沿的背侧扩张。这些发现与 Ptch1 在调节神经祖细胞的神经发生和增殖中的作用一致，