Postnatal deletion of numb/numblike reveals repair and remodeling capacity in the subventricular neurogenic niche
Postnatal deletion of numb/numblike reveals repair and remodeling capacity in the subventricular neurogenic niche
复制标题
DOI：
10.1016/j.cell.2006.10.041
复制
发表时间：
2006-12-15
期刊：
影响因子：
64.5
通讯作者：
Jan, Yuh-Nung
中科院分区：
文献类型：
--
作者：
Kuo, Chay T.;Mirzadeh, Zaman;Jan, Yuh-Nung
神经干细胞保留在出生后的室下区（SVZ），这是一个具有独特细胞结构和细胞间联系的特化神经发生微环境。尽管SVZ干细胞不断再生，但它们以及该微环境如何对局部变化作出反应尚不清楚。在此我们培育了在SVZ中具有诱导型Cre重组酶的巢蛋白 - creER(tm)转基因小鼠，并从出生后的SVZ祖细胞和室管膜细胞中去除了Numb/Numblike（胚胎神经发生的关键调节因子）。这导致大脑侧脑室完整性受到严重破坏，并确定了Numb/Numblike在调节室管膜壁完整性和SVZ神经母细胞存活方面的作用。令人惊讶的是，脑室损伤最终得到了修复：SVZ的重建和脑室壁重塑是由逃脱了Numb缺失的祖细胞介导的。我们的研究结果显示了哺乳动物大脑中的一种自我修复机制，这可能对干细胞生物学其他领域的微环境可塑性以及神经干细胞在神经退行性疾病中的治疗应用都具有重要意义。
Neural stem cells are retained in the postnatal subventricular zone (SVZ), a specialized neurogenic niche with unique cytoarchitecture and cell-cell contacts. Although the SVZ stem cells continuously regenerate, how they and the niche respond to local changes is unclear. Here we generated nestin-creER(tm) transgenic mice with inducible Cre recombinase in the SVZ and removed Numb/Numblike, key regulators of embryonic neurogenesis from postnatal SVZ progenitors and ependymal cells. This resulted in severe damage to brain lateral ventricle integrity and identified roles for Numb/Numblike in regulating ependymal wall integrity and SVZ neuroblast survival. Surprisingly, the ventricular damage was eventually repaired: SVZ reconstitution and ventricular wall remodeling were mediated by progenitors that escaped Numb deletion. Our results show a self-repair mechanism in the mammalian brain and may have implications for both niche plasticity in other areas of stem cell biology and the therapeutic use of neural stem cells in neurodegenerative diseases.