title: Aristaless Related Homeobox (ARX) Interacts with β-Catenin, BCL9, and P300 to Regulate Canonical Wnt Signaling.
abstract: Mutations in the Aristaless Related Homeobox (ARX) gene are associated with a spectrum of structural (lissencephaly) and functional (epilepsy and intellectual disabilities) neurodevelopmental disorders. How mutations in this single transcription factor can result in such a broad range of phenotypes remains poorly understood. We hypothesized that ARX functions through distinct interactions with specific transcription factors/cofactors to regulate unique target genes in different cell types. To identify ARX interacting proteins, we performed an unbiased proteomics screen and identified several components of the Wnt/β-catenin signaling pathway, including β-catenin (CTNNB1), B-cell CLL/lymphoma 9 (BCL9) and leucine rich repeat flightless interacting protein 2 (LRRFIP2), in cortical progenitor cells. Our data show that ARX positively regulates Wnt/ β-catenin signaling and that the C-terminal domain of ARX interacts with the armadillo repeats in β-catenin to promote Wnt/β-catenin signaling. In addition, we found BCL9 and P300 also interact with ARX to modulate Wnt/β-catenin signaling. These data provide new insights into how ARX can uniquely regulate cortical neurogenesis, and connect the function of ARX with Wnt/β-catenin signaling.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School Boston, Massachusetts, United States of America.
authors.forename: Il-Taeg
authors.initials: IT
authors.lastname: Cho
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School Boston, Massachusetts, United States of America.
authors.forename: Youngshin
authors.initials: Y
authors.lastname: Lim
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School Boston, Massachusetts, United States of America.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Golden
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School Boston, Massachusetts, United States of America.
authors.forename: Ginam
authors.identifier: http://orcid.org/0000-0002-7262-8716
authors.initials: G
authors.lastname: Cho
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005801:Genes, Homeobox; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology; D011247:Pregnancy; D016548:Prosencephalon / Q000196:embryology / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D040901:Proteomics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C469265:ARX protein, mouse; D048868:Adaptor Proteins, Signal Transducing; C545436:BCL9 protein, mouse; C495267:CTNNB1 protein, mouse; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; C587507:LRRFIP2 protein, mouse; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D051176:beta Catenin; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse