Neural-specific inactivation of ShcA results in increased embryonic neural progenitor apoptosis and microencephaly
Neural-specific inactivation of ShcA results in increased embryonic neural progenitor apoptosis and microencephaly
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DOI：
10.1523/jneurosci.3524-05.2006
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发表时间：
2006-07-26
影响因子：
5.3
通讯作者：
Mandell, James W.
中科院分区：
文献类型：
--
作者：
McFarland, Karen N.;Wilkes, Steven R.;Mandell, James W.
脑的大小在发育过程中受到精确的调节，并涉及神经祖细胞增殖、分化和存活的协调。衔接蛋白ShcA通过MAPK（丝裂原活化蛋白激酶）/ERK（细胞外信号调节激酶）和PI 3 K（磷脂酰肌醇3-激酶）/Akt信号通路传递来自受体酪氨酸激酶的信号。在CNS中，ShcA表达在胚胎发育期间是高的，但随着细胞分化并切换到ShcB/Sck/Sli和ShcC/N-Shc/Rai而减少。为了直接测试ShcA在脑发育中的功能，我们使用Cre/lox技术在表达nestin的神经祖细胞中表达显性负性形式的ShcA（ShcFFF）。表达ShcFFF的小鼠在整个出生后和成年期表现出脑重量降低至同窝对照的50%的脑畸形。大脑似乎受到最严重的影响，但大脑的总体结构是正常的。体重受到轻度影响，延迟达到成熟体重。在机制水平上，ShcFFF小脑畸形表型似乎主要归因于从胚胎第10.5天（E10.5）到E12整个大脑的细胞凋亡水平升高，E14.5下降。在整个出生后发育过程中，细胞凋亡保持在正常的基础水平。增殖指数没有显着改变胚胎神经上皮细胞或出生后脑室下区。在另一种使用相同nestin-Cre转基因的方法中，具有纯合floxed shc 1基因座的小鼠中ShcA的条件性缺失也显示出类似的微脑畸形表型。总之，这些数据表明ShcA在神经祖细胞存活信号传导和调节大脑大小中起关键作用。
Brain size is precisely regulated during development and involves coordination of neural progenitor cell proliferation, differentiation, and survival. The adapter protein ShcA transmits signals from receptor tyrosine kinases via MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) and PI3K ( phosphatidylinositol 3-kinase)/Akt signaling pathways. In the CNS, ShcA expression is high during embryonic development but diminishes as cells differentiate and switches to ShcB/Sck/Sli and ShcC/N-Shc/Rai. To directly test ShcA function in brain development, we used Cre/lox technology to express a dominant-negative form of ShcA (ShcFFF) in nestin-expressing neural progenitors. ShcFFF-expressing mice display microencephaly with brain weights reduced to 50% of littermate controls throughout postnatal and adult life. The cerebrum appeared most severely affected, but the gross architecture of the brain is normal. Body weight was mildly affected with a delay in reaching mature weight. At a mechanistic level, the ShcFFF microencephaly phenotype appears to be primarily attributable to elevated apoptosis levels throughout the brain from embryonic day 10.5 (E10.5) to E12, which declined by E14.5. Apoptosis remained at normal basal levels throughout postnatal development. Proliferation indices were not significantly altered in the embryonic neuroepithelium or within the postnatal subventricular zone. In another approach with the same nestin-Cre transgene, conditional deletion of ShcA in mice with a homozygous floxed shc1 locus also showed a similar microencephaly phenotype. Together, these data suggest a critical role for ShcA in neural progenitor survival signaling and in regulating brain size.