title: Huntingtin-associated protein 1 interacts with Ahi1 to regulate cerebellar and brainstem development in mice.
abstract: Joubert syndrome is an autosomal recessive disorder characterized by congenital malformation of the cerebellum and brainstem, with abnormal decussation in the brain. Mutations in the Abelson helper integration site 1 gene, which encodes the protein AHI1, have been shown to cause Joubert syndrome. In this study, we found that mouse Ahi1 formed a stable complex with huntingtin-associated protein 1 (Hap1), which is critical for neonatal development and involved in intracellular trafficking. Hap1-knockout mice showed significantly reduced Ahi1 levels, defective cerebellar development, and abnormal axonal decussation. Suppression of Ahi1 also decreased the level of Hap1; and truncated Ahi1, which corresponds to the mutations in Joubert syndrome, inhibited neurite outgrowth in neuronal culture. Reducing Hap1 expression suppressed the level and internalization of TrkB, a neurotrophic factor receptor that mediates neurogenesis and neuronal differentiation, which led to decreased TrkB signaling. These findings provide insight into the pathogenesis of Joubert syndrome and demonstrate the critical role of the Ahi1-Hap1 complex in early brain development.
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Sheng
authors.forename: Xingshun
authors.initials: X
authors.lastname: Xu
authors.forename: Yung-Feng
authors.initials: YF
authors.lastname: Lin
authors.forename: Chuan-En
authors.initials: CE
authors.lastname: Wang
authors.forename: Juan
authors.initials: J
authors.lastname: Rong
authors.forename: Dongmei
authors.initials: D
authors.lastname: Cheng
authors.forename: Junmin
authors.initials: J
authors.lastname: Peng
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Jiang
authors.forename: Shi-Hua
authors.initials: SH
authors.lastname: Li
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Li
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001933:Brain Stem / Q000002:abnormalities*; D002460:Cell Line; D002478:Cells, Cultured; D002531:Cerebellum / Q000002:abnormalities*; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D014162:Transfection
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C465818:Ahi1 protein, mouse; C490758:Hap1 protein, mouse; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins