Pten Mutations Alter Brain Growth Trajectory and Allocation of Cell Types through Elevated β-Catenin Signaling
Pten Mutations Alter Brain Growth Trajectory and Allocation of Cell Types through Elevated β-Catenin Signaling
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DOI：
10.1523/jneurosci.5272-14.2015
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发表时间：
2015-07-15
影响因子：
5.3
通讯作者：
Page, Damon T.
中科院分区：
文献类型：
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作者：
Chen, Youjun;Huang, Wen-Chin;Page, Damon T.
头部和大脑生长异常模式是自闭症谱系障碍（ASD）部分个体中重复出现的一种发现。目前尚不清楚与ASD和大脑异常生长（过度生长和生长不足）相关的风险因素是否在发育中的大脑的共同生物学途径和细胞机制上汇聚。PTEN（PTEN+/-）的杂合突变是ASD和巨头畸形的一个风险因素，PTEN编码PI3K - Akt - mTOR通路的一个负调节因子。在此，我们利用Pten（+/-）小鼠发育中的大脑皮层来研究大脑过度生长的轨迹及其潜在的细胞机制。我们发现从出生到成年都可检测到过度生长，这种过度生长是由细胞增生驱动的，并且在出生时与神经元过多相关，在成年时与神经胶质细胞过多相关。β - 连环蛋白信号在发育中的Pten（+/-）皮层中升高，而Ctnnb1（编码β - 连环蛋白）的杂合突变本身是ASD和小头畸形的一个候选基因，能够抑制Pten（+/-）皮层的过度生长。因此，Pten和β - 连环蛋白信号的平衡通过控制细胞数量来调节正常的大脑生长轨迹，这种关系的失衡会导致大脑生长异常。
Abnormal patterns of head and brain growth are a replicated finding in a subset of individuals with autism spectrum disorder (ASD). It is not known whether risk factors associated with ASD and abnormal brain growth (both overgrowth and undergrowth) converge on common biological pathways and cellular mechanisms in the developing brain. Heterozygous mutations in PTEN (PTEN+/-), which encodes a negative regulator of the PI3K-Akt-mTOR pathway, are a risk factor for ASD and macrocephaly. Here we use the developing cerebral cortex of Pten(+/-) mice to investigate the trajectory of brain overgrowth and underlying cellular mechanisms. We find that overgrowth is detectable from birth to adulthood, is driven by hyperplasia, and coincides with excess neurons at birth and excess glia in adulthood. beta-Catenin signaling is elevated in the developing Pten(+/-) cortex, and a heterozygous mutation in Ctnnb1 (encoding beta-catenin), itself a candidate gene for ASD and microcephaly, can suppress Pten(+/-) cortical overgrowth. Thus, a balance of Pten and beta-catenin signaling regulates normal brain growth trajectory by controlling cell number, and imbalance in this relationship can result in abnormal brain growth.