title: Arx together with FoxA2, regulates Shh floor plate expression.
abstract: Mutations in the Aristaless related homeodomain transcription factor (ARX) are associated with a diverse set of X-linked mental retardation and epilepsy syndromes in humans. Although most studies have been focused on its function in the forebrain, ARX is also expressed in other regions of the developing nervous system including the floor plate (FP) of the spinal cord where its function is incompletely understood. To investigate the role of Arx in the FP, we performed gain-of-function studies in the chick using in ovo electroporation, and loss-of-function studies in Arx-deficient mice. We have found that Arx, in conjunction with FoxA2, directly induces Sonic hedgehog (Shh) expression through binding to a Shh floor plate enhancer (SFPE2). We also observed that FoxA2 induces Arx through its transcriptional activation domain whereas Nkx2.2, induced by Shh, abolishes this induction. Our data support a feedback loop model for Arx function; through interactions with FoxA2, Arx positively regulates Shh expression in the FP, and Shh signaling in turn activates Nkx2.2, which suppresses Arx expression. Furthermore, our data are evidence that Arx plays a role as a context dependent transcriptional activator, rather than a primary inducer of Shh expression, potentially explaining how mutations in ARX are associated with diverse, and often subtle, defects.
authors: Department of Pathology, Brigham and Women׳s Hospital, Harvard Medical School, USA; Department of Pathology and Laboratory Medicine, Children׳s Hospital of Philadelphia, USA.
authors: Ginam
authors: G
authors: Cho
authors: Department of Pathology, Brigham and Women׳s Hospital, Harvard Medical School, USA.
authors: Youngshin
authors: Y
authors: Lim
authors: Department of Pathology, Brigham and Women׳s Hospital, Harvard Medical School, USA.
authors: Il-Taeg
authors: IT
authors: Cho
authors: Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, USA.
authors: Jacqueline C
authors: JC
authors: Simonet
authors: Department of Pathology, Brigham and Women׳s Hospital, Harvard Medical School, USA; Department of Pathology and Laboratory Medicine, Children׳s Hospital of Philadelphia, USA. Electronic address: jagolden@partners.org.
authors: Jeffrey A
authors: JA
authors: Golden
mesh_terms: D000818:Animals; D002642:Chick Embryo; D004827:Epilepsy / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000096:biosynthesis / Q000378:metabolism*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000096:biosynthesis*; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D038901:X-Linked Intellectual Disability / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D054259:Neural Tube / Q000196:embryology / Q000254:growth & development; D009687:Nuclear Proteins; D013116:Spinal Cord / Q000196:embryology*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins
chemical_list: C469265:ARX protein, mouse; C496503:Foxa2 protein, mouse; D053823:Hedgehog Proteins; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; C000715631:NKX2-2 protein, human; C000715627:Nkx2-2 protein, mouse; D009687:Nuclear Proteins; C465570:Shh protein, mouse; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715630:nkx2.2b protein, zebrafish; D051542:Hepatocyte Nuclear Factor 3-beta
keywords: Arx; Development; Floor plate; FoxA2; Neural tube; Nkx2.2; Shh; Spinal cord