title: An SNP in an ultraconserved regulatory element affects Dlx5/Dlx6 regulation in the forebrain.
abstract: Dlx homeobox genes play a crucial role in the migration and differentiation of the subpallial precursor cells that give rise to various subtypes of gamma-aminobutyric acid (GABA)-expressing neurons of the forebrain, including local-circuit cortical interneurons. Aberrant development of GABAergic interneurons has been linked to several neurodevelopmental disorders, including epilepsy, schizophrenia, Rett syndrome and autism. Here, we report in mice that a single-nucleotide polymorphism (SNP) found in an autistic proband falls within a functional protein binding site in an ultraconserved cis-regulatory element. This element, I56i, is involved in regulating Dlx5/Dlx6 homeobox gene expression in the developing forebrain. We show that the SNP results in reduced I56i activity, predominantly in the medial and caudal ganglionic eminences and in streams of neurons tangentially migrating to the cortex. Reduced activity is also observed in GABAergic interneurons of the adult somatosensory cortex. The SNP affects the affinity of Dlx proteins for their binding site in vitro and reduces the transcriptional activation of the enhancer by Dlx proteins. Affinity purification using I56i sequences led to the identification of a novel regulator of Dlx gene expression, general transcription factor 2 I (Gtf2i), which is among the genes most often deleted in Williams-Beuren syndrome, a neurodevelopmental disorder. This study illustrates the clear functional consequences of a single nucleotide variation in an ultraconserved non-coding sequence in the context of developmental abnormalities associated with disease.
authors: Center for Advanced Research in Environmental Genomics (CAREG), Department of Biology, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
authors: Luc
authors: L
authors: Poitras
authors: Man
authors: M
authors: Yu
authors: Cindy
authors: C
authors: Lesage-Pelletier
authors: Ryan B
authors: RB
authors: Macdonald
authors: Jean-Philippe
authors: JP
authors: Gagné
authors: Gary
authors: G
authors: Hatch
authors: Isabelle
authors: I
authors: Kelly
authors: Steven P
authors: SP
authors: Hamilton
authors: John L R
authors: JL
authors: Rubenstein
authors: Guy G
authors: GG
authors: Poirier
authors: Marc
authors: M
authors: Ekker
mesh_terms: D000818:Animals; D001483:Base Sequence; D002465:Cell Movement; D017124:Conserved Sequence; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D016548:Prosencephalon / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D016415:Sequence Alignment; D014158:Transcription, Genetic
chemical_list: C501120:Dlx5 protein, mouse; C100597:Dlx6 protein, mouse; D018398:Homeodomain Proteins