title: Expression at the imprinted dlk1-gtl2 locus is regulated by proneural genes in the developing telencephalon.
abstract: Imprinting is an epigenetic mechanism that restrains the expression of about 100 genes to one allele depending on its parental origin. Several imprinted genes are implicated in neurodevelopmental brain disorders, such as autism, Angelman, and Prader-Willi syndromes. However, how expression of these imprinted genes is regulated during neural development is poorly understood. Here, using single and double KO animals for the transcription factors Neurogenin2 (Ngn2) and Achaete-scute homolog 1 (Ascl1), we found that the expression of a specific subset of imprinted genes is controlled by these proneural genes. Using in situ hybridization and quantitative PCR, we determined that five imprinted transcripts situated at the Dlk1-Gtl2 locus (Dlk1, Gtl2, Mirg, Rian, Rtl1) are upregulated in the dorsal telencephalon of Ngn2 KO mice. This suggests that Ngn2 influences the expression of the entire Dlk1-Gtl2 locus, independently of the parental origin of the transcripts. Interestingly 14 other imprinted genes situated at other imprinted loci were not affected by the loss of Ngn2. Finally, using Ngn2/Ascl1 double KO mice, we show that the upregulation of genes at the Dlk1-Gtl2 locus in Ngn2 KO animals requires a functional copy of Ascl1. Our data suggest a complex interplay between proneural genes in the developing forebrain that control the level of expression at the imprinted Dlk1-Gtl2 locus (but not of other imprinted genes). This raises the possibility that the transcripts of this selective locus participate in the biological effects of proneural genes in the developing telencephalon.
authors.affiliation: IRIBHM (Institute for Interdisciplinary Research), Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Seibt
authors.forename: Olivier
authors.initials: O
authors.lastname: Armant
authors.forename: Anne
authors.initials: A
authors.lastname: Le Digarcher
authors.forename: Diogo
authors.initials: D
authors.lastname: Castro
authors.forename: Vidya
authors.initials: V
authors.lastname: Ramesh
authors.forename: Laurent
authors.initials: L
authors.lastname: Journot
authors.forename: François
authors.initials: F
authors.lastname: Guillemot
authors.forename: Pierre
authors.initials: P
authors.lastname: Vanderhaeghen
authors.forename: Tristan
authors.initials: T
authors.lastname: Bouschet
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000378:metabolism; D002135:Calcium-Binding Proteins; D018507:Gene Expression Regulation, Developmental; D056426:Genetic Loci / Q000235:genetics*; D018392:Genomic Imprinting / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D013687:Telencephalon / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C499317:Ascl1 protein, mouse; C512925:Dlk1 protein, mouse; C102938:Neurog2 protein, mouse