Atypical Neocortical Development in the Cited2 Conditional Knockout Leads to Behavioral Deficits Associated with Neurodevelopmental Disorders.
Atypical Neocortical Development in the Cited2 Conditional Knockout Leads to Behavioral Deficits Associated with Neurodevelopmental Disorders.
复制标题
引用2条件性基因敲除中的非典型新皮质发育导致与神经发育障碍相关的行为缺陷。
DOI：
10.1016/j.neuroscience.2020.12.009
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发表时间：
2021
期刊：
影响因子：
3.3
通讯作者：
MacDonald,JessicaL
中科院分区：
文献类型：
--
作者：
Wagner,NikolausR;MacDonald,JessicaL
哺乳动物的新皮质由单层神经上皮细胞发育而来，形成由分化的神经元和神经胶质细胞组成的六层异质马赛克。这一过程需要时间和空间受限的转录因子和表观遗传调控因子的复杂编排。即使这种调节的微小干扰也会改变新皮质的形成和功能，导致神经发育障碍。对于新皮质的精确发育至关重要的一个表观遗传调节因子是CITED2(CBP/p300相互作用的富含ED末端的反式激活因子)。在新皮质浅层的产生过程中，Cited2由脑室下区的中间前体细胞高度表达。前脑特异的Cited2条件性敲除(CKO)在胚胎时期表现出中间祖细胞的增殖减少，导致出生后浅层厚度的减少和胼胝体体积的减少。此外，Cited2cKO显示平衡的新皮质区域化中断，躯体感觉新皮质长度特定缩短，精确的、区域特定的神经元连接失调。在这里，我们探索这种异常的新皮质发育所导致的行为后果。我们证明，Cited2cKO小鼠在出生时母体分离诱导的超声发声(USVs)减少，成年后重复声音惊吓后养育行为和缺乏适应能力增加。他们没有表现出焦虑样行为、整体运动活动或社交互动的变化。结合形态、分子和连接障碍，这些结果表明Cited2cKO新皮质是研究神经发育和神经解剖障碍与人类神经发育障碍相关机制的理想系统。
The mammalian neocortex develops from a single layer of neuroepithelial cells to form a six-layer heterogeneous mosaic of differentiated neurons and glial cells. This process requires a complex choreography of temporally and spatially restricted transcription factors and epigenetic regulators. Even subtle disruptions in this regulation can alter the way the neocortex forms and functions, leading to a neurodevelopmental disorder. One epigenetic regulator that is essential for the precise development of the neocortex is CITED2 (CBP/p300InteractingTransactivator withED-rich termini).Cited2is highly expressed by intermediate progenitor cells in the subventricular zone during the generation of the superficial layers of the neocortex. A forebrain-specific conditional knockout ofCited2(cKO) exhibits reduced proliferation of intermediate progenitor cells embryonically, leading to reduced thickness of the superficial layers and reduced corpus callosum (CC) volume postnatally. Further, theCited2cKO display disruptions in balanced neocortical arealization, with a specific reduction in the somatosensory neocortical length, and dysregulation of precise, area-specific neuronal connectivity. Here, we explore the behavioral consequences resulting from this aberrant neocortical development. We demonstrate thatCited2cKO mice display decreased maternal separation-induced ultrasonic vocalizations (USVs) as neonates, and an increase in rearing behavior and lack of habituation following repeated acoustic startle as adults. They do not display alterations in anxiety-like behavior, overall locomotor activity, or social interactions. Together with the morphological, molecular, and connectivity disruptions, these results identify theCited2cKO neocortex as an ideal system to study mechanisms underlying neurodevelopmental and neuroanatomical disruptions with relevance to human neurodevelopmental disorders.