Department of Anesthesiology, Northwestern University Feinberg School of Medicine, 303 E, Chicago Avenue, Ward 10-070, Chicago, IL 60611, USA.
Neural Dev. 2011 Feb 1;6:6. doi: 10.1186/1749-8104-6-6.
Insm1 is a zinc-finger transcription factor transiently expressed throughout the developing nervous system in late progenitors and nascent neurons. Insm1 is also highly expressed in medulloblastomas and other neuroendocrine tumors.
We generated mice lacking the Insm1 gene and used them to elucidate its role in neurogenic proliferation of the embryonic olfactory epithelium. We found that deletion of Insm1 results in more apical cells and fewer nascent and mature neurons. In the embryonic olfactory epithelium of Insm1 mutants we detect fewer basal progenitors, which produce neurons, and more apical progenitors, which at this stage produce additional progenitors. Furthermore, in the mutants we detect fewer progenitors expressing NEUROD1, a marker of terminally dividing, neuronogenic (neuron-producing) progenitors (immediate neuronal precursors), and more progenitors expressing ASCL1, a marker of the transit amplifying progenitors that migrate from the apical to the basal edges of the epithelium while dividing to generate the terminal, neuronogenic progenitors. Finally, with timed administration of nucleoside analogs we demonstrate that the Insm1 mutants contain fewer terminally dividing progenitors at embryonic day 12.5.
Altogether, these results suggest a role for Insm1 in promoting the transition of progenitors from apical and proliferative to basal, terminal and neuronogenic. This role appears partially conserved with that of its nematode ortholog, egl-46. The similar effects of Insm1 deletion on progenitors of embryonic olfactory epithelium and cortex point to striking parallels in the development of these neuroepithelia, and particularly between the basal progenitors of olfactory epithelium and the subventricular zone progenitors of cortex.
Insm1 是一种锌指转录因子，在发育中的神经系统中晚期祖细胞和新生神经元中短暂表达。Insm1 在髓母细胞瘤和其他神经内分泌肿瘤中也高度表达。
我们生成了缺乏 Insm1 基因的小鼠，并利用它们阐明了 Insm1 在胚胎嗅上皮神经发生增殖中的作用。我们发现，Insm1 的缺失导致更多的顶端细胞和更少的新生和成熟神经元。在 Insm1 突变体的胚胎嗅上皮中，我们检测到更少的产生神经元的基底祖细胞，而更多的顶端祖细胞，在这个阶段，产生更多的祖细胞。此外，在突变体中，我们检测到更少的表达 NEUROD1 的祖细胞，NEUROD1 是终末分裂、神经发生（产生神经元）祖细胞的标志物（即直接神经元前体），更多的表达 ASCL1 的祖细胞，ASCL1 是从顶端到上皮基底边缘迁移并分裂产生终末、神经发生祖细胞的过渡扩增祖细胞的标志物。最后，通过核苷类似物的定时给药，我们证明 Insm1 突变体在胚胎 12.5 天时含有更少的终末分裂祖细胞。
总的来说，这些结果表明 Insm1 在促进祖细胞从顶端和增殖到基底、终末和神经发生的转变中起作用。这个作用在一定程度上与线虫同源物 egl-46 的作用相似。Insm1 缺失对胚胎嗅上皮和皮质祖细胞的相似影响表明这些神经上皮的发育之间存在惊人的相似之处，特别是在嗅上皮的基底祖细胞和皮质的室下区祖细胞之间。
