Elucidation of the mechanism of autism onset based on testis-brain linkage and development of novel therapies

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K19599
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 56:Surgery related to the biological and sensory functions and related fields
• Research Institution: Kanazawa University
• Principal Investigator: Nishiyama Masaaki 金沢大学, 新学術創成研究機構, 教授 (50423562)
• Project Period (FY): 2022-06-30 – 2024-03-31
• Keywords: 精巣－脳連関 / 自閉症

Outline of Final Research Achievements

We examined the function of CHD8 during spermatogenesis by establishing a germ-cell specific Chd8 loss-of-function mouse model. We observed that Chd8 ablation in germ cells leads to testicular atrophy and infertility. Upon closer inspection, CHD8-deficient germ cells exhibited two independent phenotypes: a gradual depletion of undifferentiated spermatogonia and acute differentiation arrest before the pachytene stage during meiotic prophase I. Transcriptional analyses demonstrated that CHD8 is required for extensive activation of spermatogenic genes in spermatogonia. We confirmed that CHD8 is associated with the activation of genes required for meiosis, namely H3K4me3 histone methyltransferase genes, meiotic cohesin genes, HORMA domain-containing genes, synaptonemal complex genes, and DNA damage response (DDR) genes.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

クロマチンリモデラーであるCHD8は、自閉スペクトラム症（ASD）で頻繁に変異が見つかることから、主に自閉症原因遺伝子として知られている。一方、CHD8は、造血幹細胞、脂肪細胞、腸管細胞など、様々な非神経臓器の発生に必須な役割を果たすことが報告されている。本研究では、精子形成におけるCHD8の機能を明らかにしようとした。その理由のひとつは、自閉症を含む知的障害と生殖能力の低下との間に疫学的関連があることである。われわれの結果は、減数第一分裂前期の正常な進行のために、ヒストンメチルトランスフェラーゼを制御するCHD8の重要な機能を明らかにするものである。