title: Hes1 expression is reduced in Tbx1 null cells and is required for the development of structures affected in 22q11 deletion syndrome.
abstract: 22q11 deletion syndrome (22q11DS) is characterised by aberrant development of the pharyngeal apparatus and the heart with haploinsufficiency of the transcription factor TBX1 being considered the major underlying cause of the disease. Tbx1 mutations in mouse phenocopy the disorder. In order to identify the transcriptional dysregulation in Tbx1-expressing lineages we optimised fluorescent-activated cell sorting of beta-galactosidase expressing cells (FACS-Gal) to compare the expression profile of Df1/Tbx1(lacZ) (effectively Tbx1 null) and Tbx1 heterozygous cells isolated from mouse embryos. Hes1, a major effector of Notch signalling, was identified as downregulated in Tbx1(-)(/)(-) mutants. Hes1 mutant mice exhibited a partially penetrant range of 22q11DS-like defects including pharyngeal arch artery (PAA), outflow tract, craniofacial and thymic abnormalities. Similar to Tbx1 mice, conditional mutagenesis revealed that Hes1 expression in embryonic pharyngeal ectoderm contributes to thymus and pharyngeal arch artery development. These results suggest that Hes1 acts downstream of Tbx1 in the morphogenesis of pharyngeal-derived structures.
authors.affiliation: Molecular Medicine Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Kelly Lammerts
authors.initials: KL
authors.lastname: van Bueren
authors.forename: Irinna
authors.initials: I
authors.lastname: Papangeli
authors.forename: Francesca
authors.initials: F
authors.lastname: Rochais
authors.forename: Kerra
authors.initials: K
authors.lastname: Pearce
authors.forename: Catherine
authors.initials: C
authors.lastname: Roberts
authors.forename: Amelie
authors.initials: A
authors.lastname: Calmont
authors.forename: Dorota
authors.initials: D
authors.lastname: Szumska
authors.forename: Robert G
authors.initials: RG
authors.lastname: Kelly
authors.forename: Shoumo
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scambler
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001934:Branchial Region / Q000196:embryology* / Q000378:metabolism; D002875:Chromosomes / Q000235:genetics; D004622:Embryo, Mammalian / Q000378:metabolism; D006321:Heart / Q000196:embryology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D017384:Sequence Deletion; D013577:Syndrome; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D013950:Thymus Gland / Q000196:embryology* / Q000378:metabolism; D000072056:Transcription Factor HES-1; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D020825:T-Box Domain Proteins; D000072056:Transcription Factor HES-1; D001616:beta-Galactosidase; C489734:Hes1 protein, mouse; C491573:Tbx1 protein, mouse