title: Loss of Ahi1 affects early development by impairing BM88/Cend1-mediated neuronal differentiation.
abstract: 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.
authors: Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
authors: Ling
authors: L
authors: Weng
authors: Yung-Feng
authors: YF
authors: Lin
authors: Alina L
authors: AL
authors: Li
authors: Chuan-En
authors: CE
authors: Wang
authors: Sen
authors: S
authors: Yan
authors: Miao
authors: M
authors: Sun
authors: Marta A
authors: MA
authors: Gaertig
authors: Naureen
authors: N
authors: Mitha
authors: Jun
authors: J
authors: Kosaka
authors: Taketoshi
authors: T
authors: Wakabayashi
authors: Xingshun
authors: X
authors: Xu
authors: Beisha
authors: B
authors: Tang
authors: Shihua
authors: S
authors: Li
authors: Xiao-Jiang
authors: XJ
authors: Li
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D019417:Hindlimb Suspension / Q000502:physiology; D006801:Humans; D007031:Hypothalamus / Q000166:cytology / Q000254:growth & development; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics; D020932:Nerve Growth Factor / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000172:deficiency*; D051381:Rats; D013550:Swimming; D014162:Transfection
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C465818:Ahi1 protein, mouse; C496858:Cend1 protein, mouse; C490758:Hap1 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D020932:Nerve Growth Factor
references: J Cell Biol. 1990 Apr;110(4):1333-9
references: 2157719
references: J Neurosci. 2010 Jun 30;30(26):8759-68
references: 20592197
references: Nat Genet. 2010 Feb;42(2):175-80
references: 20081859
references: J Trop Pediatr. 2010 Jun;56(3):209-12
references: 19755534
references: Cell Mol Life Sci. 2006 Nov;63(22):2642-60
references: 17041811
references: J Biol Chem. 2009 Apr 17;284(16):10639-49
references: 19240035
references: FASEB J. 2010 Aug;24(8):3066-82
references: 20371615
references: J Neurochem. 2005 Jul;94(2):502-9
references: 15998300
references: Neurobiol Dis. 2013 May;53:3-9
references: 23123588
references: Hum Mol Genet. 2002 Apr 15;11(8):945-59
references: 11971876
references: J Neurosci. 2006 May 31;26(22):6019-30
references: 16738245
references: J Biol Chem. 2006 Nov 3;281(44):33606-20
references: 16893893
references: Eur J Neurosci. 2004 Nov;20(10):2509-23
references: 15548196
references: J Neurosci. 2003 Jul 30;23(17):6956-64
references: 12890790
references: Cell Adh Migr. 2009 Jan-Mar;3(1):71-6
references: 19262167
references: J Child Neurol. 1998 Aug;13(8):391-7
references: 9721895
references: Neurosci Biobehav Rev. 2007;31(1):103-14
references: 16982094
references: J Biol Chem. 1995 Jun 9;270(23):14201-8
references: 7775480
references: Stem Cells. 2008 Jul;26(7):1796-807
references: 18499894
references: Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):19126-31
references: 20956301
references: J Virol. 1989 May;63(5):2088-98
references: 2539505
references: Eur J Hum Genet. 2007 Sep;15(9):988-91
references: 17473831
references: Trends Cell Biol. 2009 Apr;19(4):147-55
references: 19269181
references: J Virol. 2002 Sep;76(18):9046-59
references: 12186888
references: Mol Cell Neurosci. 2000 Aug;16(2):168-83
references: 10924259
references: J Neurochem. 2010 Mar;112(5):1235-48
references: 20002527
references: Neurosci Biobehav Rev. 2005;29(4-5):571-625
references: 15890404
references: Nature. 1995 Nov 23;378(6555):398-402
references: 7477378
references: J Child Neurol. 1999 Sep;14(9):583-90; discussion 590-1
references: 10488903
references: Science. 2002 May 31;296(5573):1648-9
references: 12040181
references: Mol Cell Neurosci. 2010 May;44(1):15-29
references: 20153830
references: Nat Genet. 2004 Sep;36(9):1008-13
references: 15322546
references: J Comp Neurol. 2008 Nov 10;511(2):238-56
references: 18785627
references: Hum Mol Genet. 2009 Oct 15;18(20):3926-41
references: 19625297
references: Eur J Hum Genet. 2006 Oct;14(10):1111-9
references: 16773125
references: Hum Mol Genet. 2008 Dec 15;17(24):3887-96
references: 18782849
references: Trends Pharmacol Sci. 2005 Jan;26(1):1-3
references: 15629196
references: J Clin Invest. 2008 Aug;118(8):2785-95
references: 18636121
references: Mol Cell Endocrinol. 2010 Jul 8;323(1):115-23
references: 20385202
references: Biol Psychiatry. 1991 Feb 1;29(3):287-94
references: 2015333
references: Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17861-6
references: 17971443
references: Nat Med. 2011 Jun;17(6):726-31
references: 21623382
references: Am J Hum Genet. 2004 Dec;75(6):979-87
references: 15467982
references: Hum Mol Genet. 2010 Apr 1;19(7):1379-86
references: 20071346