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.

A Novel Hap1–Tsc1 Interaction Regulates Neuronal mTORC1 Signaling and Morphogenesis in the Brain

“…Hap1 may regulate the trafficking of microtubule-and membrane-associated protein cargoes in neurons. In this function, Hap1 is thought to promote protein recycling and prevent protein degradation (Rong et al, 2007;Sheng et al, 2008). Interestingly, Hap1 expression appears to be largely limited to neural tissues (Dragatsis et al, 2000).…”

DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

“…Hap1 was initially recognized for its binding to polyglutamine-expanded huntingtin (Htt), the protein responsible for Huntington's disease (3). Because Hap1 is expressed at various levels in different types of neurons (1,(4)(5)(6)(7)(8), it is likely involved in cell type-specific functions of the brain. For example, Hap1 is abundantly expressed in the hypothalamus, and its expression in the hypothalamus influences the central control of feeding (9); as a direct result, mice lacking Hap1 are malnourished and die in the early postnatal period (5, 10, 11).…”

Association of copy number variation in the AHI1 gene with risk of obesity in the Chinese population

“…Many groups have identified that AHI1 mutations are a frequent cause of disease in patients with specific forms of Joubert syndrome (31,32,33), an autosomal recessive neurodevelopmental disorder. Distribution of AHI1 in the embryonic and postembryonic mouse tissues has been reported, and both protein and mRNA studies have shown that AHI1 is highly distributed in several brain areas implicated in feeding and metabolic regulation, including the hypothalamus and nucleus tractus solitarius in the brain stem (31,34,35,36).…”

“…However, two recent reports have demonstrated increased expression of AHI1 protein in the hypothalamus of insulin-treated mice, suggesting a role for AHI1 as a putative central regulator for glucose metabolism and energy homeostasis (13,36). Also, one group reported a significant association between variants in the AHI1 gene and BMI in a Caucasian population of type 2 diabetes patients (12).…”