TRIM32 Deficiency Impairs the Generation of Pyramidal Neurons in Developing Cerebral Cortex
Yan-Yun Sun,
Wen-Jin Chen,
Ze-Ping Huang,
Gang Yang,
Ming-Lei Wu,
De-En Xu,
Wu-Lin Yang,
Yong-Chun Luo,
Zhi-Cheng Xiao,
Ru-Xiang Xu,
Quan-Hong Ma
Affiliations
Yan-Yun Sun
Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215123, China
Wen-Jin Chen
Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
Ze-Ping Huang
Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215123, China
Gang Yang
Lab Center, Medical College of Soochow University, Suzhou 215123, China
Ming-Lei Wu
Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215123, China
De-En Xu
Wuxi No. 2 People’s Hospital, Wuxi 214001, China
Wu-Lin Yang
Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
Yong-Chun Luo
Department of Neurosurgery, First Medical Center of Chinese PLA General Hospital, Beijing 100028, China
Zhi-Cheng Xiao
Department of Anatomy and Developmental Biology, Monash University, Clayton 3800, Australia
Ru-Xiang Xu
Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
Quan-Hong Ma
Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215123, China
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.
