RGD Reference Report - Loss of Ahi1 affects early development by impairing BM88/Cend1-mediated neuronal differentiation. - Rat Genome Database

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Loss of Ahi1 affects early development by impairing BM88/Cend1-mediated neuronal differentiation.

Authors: Weng, L  Lin, YF  Li, AL  Wang, CE  Yan, S  Sun, M  Gaertig, MA  Mitha, N  Kosaka, J  Wakabayashi, T  Xu, X  Tang, B  Li, S  Li, XJ 
Citation: Weng L, etal., J Neurosci. 2013 May 8;33(19):8172-84. doi: 10.1523/JNEUROSCI.0119-13.2013.
RGD ID: 11537396
Pubmed: PMID:23658157   (View Abstract at PubMed)
PMCID: PMC3703472   (View Article at PubMed Central)
DOI: DOI:10.1523/JNEUROSCI.0119-13.2013   (Journal Full-text)

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 AHI1 mutations 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. Nerve growth factor 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 (cell cycle exit and neuronal differentiation protein 1)/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 Ahi1 can 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 in Ahi1-associated hypothalamic neuronal differentiation in early development, giving us fresh insight into the mechanism behind the delayed development in Joubert syndrome.

Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
protein binding  IPIHap1 (Rattus norvegicus)11537396 RGD 
protein binding  IPIAhi1 (Rattus norvegicus)11537396 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ahi1  (Abelson helper integration site 1)
Hap1  (huntingtin-associated protein 1)

Additional Information