TRIM32 Deficiency Impairs the Generation of Pyramidal Neurons in Developing Cerebral Cortex.
TRIM32 Deficiency Impairs the Generation of Pyramidal Neurons in Developing Cerebral Cortex.
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TRIM32 缺陷会损害大脑皮层发育中锥体神经元的生成
作者：
Sun YY;Chen WJ;Huang ZP;Yang G;Wu ML;Xu DE;Yang WL;Luo YC;Xiao ZC;Xu RX;Ma QH
兴奋性-抑制性失衡(E/I)是自闭症谱系障碍(ASD)的基本发病机制。TRIM32是一种与ASD遗传相关的风险基因。缺乏TRIM32会导致小鼠抑制性GABA能中间神经元的生成受损，神经网络过度兴奋，以及孤独症样行为，强调了TRIM32在维持E/I平衡中的作用，但尽管TRIM32在调节培养的小鼠神经前体细胞(NPC)的增殖和分化方面有报道，但TRIM32在大脑皮层发育，特别是在兴奋性锥体神经元的产生中的作用仍不清楚。本研究观察到，TRIM32缺乏导致不同层次的皮质神经元数量减少，放射状胶质细胞(RGC)和中间前体细胞(IPC)池大小减少。我们进一步证明，TRIM32缺乏会损害视网膜节细胞和内皮祖细胞的自我更新，表现为增殖和有丝分裂减少。TRIM32缺乏也影响或影响皮质神经元的形成。结果，TRIM32基因缺陷的小鼠显示出较小的大脑尺寸。在分子水平上，RNAseq分析表明TRIM32缺陷小鼠的Notch信号减少。因此，本研究表明TRIM32在锥体神经元的发生中起作用。兴奋性锥体神经元的生成受损可能解释了TRIM32缺陷小鼠观察到的高兴奋性。
Excitatory-inhibitory imbalance (E/I) is a fundamental mechanism underlying autism spectrum disorders (ASD). TRIM32 is a risk gene genetically associated with ASD. The absence of TRIM32 causes impaired generation of inhibitory GABAergic interneurons, neural network hyperexcitability, and autism-like behavior in mice, emphasizing the role of TRIM32 in maintaining E/I balance, but despite the description of TRIM32 in regulating proliferation and differentiation of cultured mouse neural progenitor cells (NPCs), the role of TRIM32 in cerebral cortical development, particularly in the production of excitatory pyramidal neurons, remains unknown. The present study observed that TRIM32 deficiency resulted in decreased numbers of distinct layer-specific cortical neurons and decreased radial glial cell (RGC) and intermediate progenitor cell (IPC) pool size. We further demonstrated that TRIM32 deficiency impairs self-renewal of RGCs and IPCs as indicated by decreased proliferation and mitosis. A TRIM32 deficiency also affects or influences the formation of cortical neurons. As a result, TRIM32-deficient mice showed smaller brain size. At the molecular level, RNAseq analysis indicated reduced Notch signalling in TRIM32-deficient mice. Therefore, the present study indicates a role for TRIM32 in pyramidal neuron generation. Impaired generation of excitatory pyramidal neurons may explain the hyperexcitability observed in TRIM32-deficient mice.
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