The Role Of Ahil In Pathogenesis Of Joubert Syndrome

Mutations in the Abelson helper integration site-1(AHI1) gene result in N-terminal Ahi1fragments and cause Joubert syndrome, an autosomal recessive brain malformation disorder associated with delayed development. How AHI1mutations lead to delayed development remains unclear. Here we report that full-length, but not N-terminal, Ahi1binds Hap1, a huntingtin-associated protein that is essential for the postnatal survival of mice, and that this binding is regulated during neuronal differentiation by nerve growth factor (NGF). NGF induces dephosphorylation of Hap1A and decreases its association with Ahi1, correlating with increased Hap1A distribution in neurite tips. Consistently, Ahi1associates with phosphorylated Hap1A in cytosolic, but not in synaptosomal, fractions isolated from mouse brain, suggesting that Ahi1functions mainly in the soma of neurons. Mass spectrometry analysis of cytosolic Ahil immunopreciptates reveals that Ahi1also binds Cend1/BM88, a neuronal protein that mediates neuronal differentiation and is highly expressed in postnatal mouse brain. Loss of Ahil reduces the levels of Cendl in the hypothalamus of Ahil KO mice, which show retarded growth during postnatal days. Overexpressed Ahi1can stabilize Cendl in cultured cells. Furthermore, overexpression of Cendl can rescue the neurite extension defects of hypothalamic neurons from Ahil KO mice. Our findings suggest that Cendl is involved in Ahil-associated hypothalamic neuronal differentiation in early development, giving us fresh insight into the mechanism behind the delayed development in Joubert syndrome.27figures,3tables,79references.