title: Xenopus aristaless-related homeobox (xARX) gene product functions as both a transcriptional activator and repressor in forebrain development.
abstract: Mutations in the aristaless-related homeobox (ARX) gene have been found in patients with a variety of X-linked mental retardation syndromes with forebrain abnormalities, including lissencephaly. Arx is expressed in the developing mouse, Xenopus, and zebrafish forebrain. We have used whole-mount in situ hybridization, overexpression, and loss-of-function studies to investigate the involvement of xArx in Xenopus brain development. We verified that xArx is expressed in the prospective diencephalon, as the forebrain is patterned and specified during neural plate stages. Expression spreads into the ventral and medial telencephalon as development proceeds through neural tube and tadpole stages. Overexpression of xArx resulted in morphological abnormalities in forebrain development, including loss of rostral midline structures, syn- or anophthalmia, dorsal displacement of the nasal organ, and ventral neural tube hyperplasia. Additionally, there is a delay in expression of many molecular markers of brain and retinal development. However, expression of some markers, dlx5 and wnt8b, was enhanced in xArx-injected embryos. Loss-of-function experiments indicated that xArx was necessary for normal forebrain development. Expansion of wnt8b expression depended on xArx function as a transcriptional repressor, whereas ectopic expression of dlx5, accompanied by development of ectopic otic structures, depended on function of Arx as a transcriptional activator. These results suggest that Arx acts as a bifunctional transcriptional regulator in brain development.
authors.affiliation: Center for Molecular and Human Genetics, Columbus Children's Research Institute, 700 Children's Drive, Columbus, OH 43205, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Seufert
authors.forename: Nichole L
authors.initials: NL
authors.lastname: Prescott
authors.forename: Heithem M
authors.initials: HM
authors.lastname: El-Hodiri
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology; D018076:DNA, Complementary / Q000378:metabolism; D004027:Diencephalon / Q000378:metabolism; D000089662:Doublecortin Protein; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D017403:In Situ Hybridization; D008856:Microscopy, Fluorescence; D009432:Neural Crest / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D016548:Prosencephalon / Q000196:embryology*; D012313:RNA / Q000378:metabolism; D013687:Telencephalon / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D051153:Wnt Proteins; D029867:Xenopus Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D014982:Xenopus laevis; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: C469264:ARX protein, human; D018076:DNA, Complementary; C000714847:Dcx protein, mouse; C501121:Dlx5 protein, Xenopus; C501120:Dlx5 protein, mouse; D000089662:Doublecortin Protein; D018398:Homeodomain Proteins; D016376:Oligonucleotides, Antisense; D014157:Transcription Factors; D051153:Wnt Proteins; C490602:Wnt8b protein, Xenopus; D029867:Xenopus Proteins; C502721:aristaless-related homeobox protein, Xenopus; C501122:dlx5a protein, zebrafish; D049452:Green Fluorescent Proteins; D012313:RNA; D001616:beta-Galactosidase