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SETD2’s function in cortical development revealed, providing new way for profoundly understanding pathogeneses of Sotos-like syndrome and ASD
Author:  Date:2021-03-09  Clicks:

Science Advances recently published an article entitled Abnormal Neocortex Arealization and Sotos-like Syndrome-associated Behavior in Setd2 Mutant Mice, which was written collectively by the research teams of Zhou Yan at the Frontier Science Center for Immunology and Metabolism and Wu Min from the Medical Research Institute at the School of Medicine of Wuhan University (WHU).

The paper’s first author is Ph.D. student Xu Lichao (College of Life Sciences, WHU), with Prof. Zhou Yan and Prof. Wu Min as the co-corresponding authors. The research was funded by the National Key R&D Program of China, the National Natural Science Foundation of China, Frontier Science Center for Immunology and Metabolism and the State Key Laboratory of Medical Molecular Biology. Prof. Xu Fuqiang (Institute of Physics and Mathematics, Chinese Academy of Sciences), Prof. Wu Xudong (Tianjin Medical University) also contributed to this work.

The mammalian cerebral cortex (neocortex), the most complex structure in nature, consists mainly of six layers of projection neurons. The neocortex is tangentially subdivided into four key functional areas, including the primary motor cortex, visual cortex, somatosensory cortex, and auditory cortex, which realize the function of cognition, autonomous movements, and sensory perception. The formation and specification of key functional areas within the neocortex are called neocortical area patterning (arealization)the deficiency of which has close connections with neurodevelopmental conditions. Autism spectrum disorder (ASD) is considered a neurodevelopmental condition featuring deficiencies in social interaction and communication and repetitive and restricted patterns of behaviors. Neuroanatomical and imaging studies have identified cortical enlargement in a substantial number of autistic children’s frontal lobes. The Sotos-like syndrome is an overgrowth syndrome with clinical characteristics of intellectual disability, speech delay, macrocephaly, facial dysmorphism, and ASD. SETD2, the methyltransferase for histone 3 lysine-36 trimethylation (H3K36me3), shows loss-of-function mutation in some ASD patients and Sotos-like syndrome patients. However, the function of SETD2 for cortical development, social behaviors, and the pathogenesis of the Sotos-like syndrome remains poorly understood.

During their research, the authors discovered that SETD2’ s conditional knockout in mice’s cortices led to defects of cortical arealization and cortico-thalamo projections. SETD2-loss-of-function mice conduct abnormal behaviors, such as deficiencies of social interaction, spatial memory and motor learning, reminiscent of patients with Sotos-like syndrome or ASD. As for the molecular mechanism, SETD2 maintains the expression of clustered protocadherin genes in an H3K36me3 methyltransferase–dependent manner. This research is the first to reveal the functions of SETD2 and SETD2-mediated H3K36me3 modifications in cortical development in a systemic manner, especially in determining that the neocortical area patterning and epigenetic modification are crucial to the patterning of the cerebral cortex. The results offer new insights and an animal model for a deeper understanding of the pathogoneses of Sotos-like syndrome and ASD.


Link to the paper: https://advances.sciencemag.org/content/7/1/eaba1180

Written by: Zhao Jun

Rewritten by: Zhang Ruoxi

Editted by: Shi Shang


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