title: A chicken model for DGCR6 as a modifier gene in the DiGeorge critical region.
abstract: DGCR6 is the most centromeric gene in the human DiGeorge critical region and is the only gene in the region with a second functional copy on a repeat localized more distally on chromosome 22. We isolated the chicken ortholog of DGCR6 and showed an embryonic expression pattern that is initially broad but becomes gradually restricted to neural crest cell derivatives of the cardiovasculature. Retrovirus based gene transduction was used to deliver sense and antisense messages to premigrating neural crest cells in vivo. Embryos in which DGCR6 expression was attenuated revealed cardiovascular anomalies reminiscent of those found in DiGeorge syndrome. Moreover, the expression profiles of three other genes from the DiGeorge critical region, TBX-1, UFD1L, and HIRA, were shown to be altered in this model. TBX-1 and UFD1L levels were increased, whereas HIRA was decreased in the hearts and pharyngeal arches of embryos treated with antisense or partial sense constructs, but not with sense constructs for DGCR6. The expression changes were transient and followed the normal DGCR6 expression profile. These data show that neural crest cells might have a role in the distribution of modulator signals to the heart and pharyngeal arches. Moreover, it shows a repressor function for DGCR6 on the expression of TBX-1 and UFD1L. For the first time, DiGeorge syndrome is shown to be a contiguous gene syndrome in which not only several genes from the critical region, but also different cell types within the embryo, interact in the development of the phenotype.
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Beerend P
authors.initials: BP
authors.lastname: Hierck
authors.forename: Danil G M
authors.initials: DG
authors.lastname: Molin
authors.forename: Marit J
authors.initials: MJ
authors.lastname: Boot
authors.forename: Robert E
authors.initials: RE
authors.lastname: Poelmann
authors.forename: Adriana C
authors.initials: AC
authors.lastname: Gittenberger-de Groot
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002319:Cardiovascular System / Q000033:anatomy & histology / Q000254:growth & development; D002642:Chick Embryo; D002645:Chickens / Q000235:genetics*; D002892:Chromosomes, Human, Pair 22; D004062:DiGeorge Syndrome / Q000235:genetics*; D016326:Extracellular Matrix Proteins; D018507:Gene Expression Regulation, Developmental; D005809:Genes, Regulator; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000737:chemistry / Q000235:genetics; D016415:Sequence Alignment
chemical_list: C101273:DGCR6 protein, human; C498400:Dgcr6 protein, mouse; D016326:Extracellular Matrix Proteins; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D011506:Proteins