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Author Notes:

Correspondence should be addressed to: Xiao-Jiang Li, Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, Georgia 30322. Phone: (404) 727-3290; Fax: (404) 727-3949; xli2@emory.edu


Research Funding:

L.W. was supported in part by the China Scholarship Council. This work was supported by grants from the National Institutes of Health (NS036232, NS041669 and NS045016), the National Natural Science Foundation of China (81071095 and 81120108011), National Science Council(NSC 101-2320-B-038-028), and The State Key Laboratory of Molecular Developmental Biology, China.

Loss of Ahi1 Affects Early Development by Impairing BM88/Cend1-mediated Neuronal Differentiation

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Journal Title:

Journal of Neuroscience Nursing


Volume 33, Number 19


, Pages 8172-8184

Type of Work:

Article | Final Publisher PDF


Mutations in the Abelson helper integration site-1 (AHI1) gene result in N-terminal Ahi1 fragments 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, Ahi1 binds 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, Ahi1 associates with phosphorylated Hap1A in cytosolic, but not in synaptosomal, fractions isolated from mouse brain, suggesting that Ahi1 functions mainly in the soma of neurons. Mass spectrometry analysis of cytosolic Ahi1 immunoprecipitates reveals that Ahi1 also binds Cend1/BM88, a neuronal protein that mediates neuronal differentiation and is highly expressed in postnatal mouse brain. Loss of Ahi1 reduces the levels of Cend1 in the hypothalamus of Ahi1 KO mice, which show retarded growth during postnatal days. Overexpressed Ahi1can stabilize Cend1 in cultured cells. Furthermore, overexpression of Cend1 can rescue the neurite extension defects of hypothalamic neurons from Ahi1 KO mice. Our findings suggest that Cend1 is involved inAhi1-associated hypothalamic neuronal differentiation in early development, giving us fresh insight into the mechanism behind the delayed development in Joubert syndrome.

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© 2013 the authors

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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