title: Dose-dependent interaction of Tbx1 and Crkl and locally aberrant RA signaling in a model of del22q11 syndrome.
abstract: 22q11 deletion (del22q11) syndrome is characterized genetically by heterozygous deletions within chromosome 22q11 and clinically by a constellation of congenital malformations of the aortic arch, heart, thymus, and parathyroid glands described as DiGeorge syndrome (DGS). Here, we report that compound heterozygosity of mouse homologs of two 22q11 genes, CRKL and TBX1, results in a striking increase in the penetrance and expressivity of a DGS-like phenotype compared to heterozygosity at either locus. Furthermore, we show that these two genes have critical dose-dependent functions in pharyngeal segmentation, patterning of the pharyngeal apparatus along the anteroposterior axis, and local regulation of retinoic acid (RA) metabolism and signaling. We can partially rescue one salient feature of DGS in Crkl+/-;Tbx1+/- embryos by genetically reducing the amount of RA produced in the embryo. Thus, we suggest that del22q11 is a contiguous gene syndrome involving dose-sensitive interaction of CRKL and TBX1 and locally aberrant RA signaling.
authors.affiliation: The Ben May Institute for Cancer Research and Center for Molecular Oncology, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Guris
authors.forename: Gregg
authors.initials: G
authors.lastname: Duester
authors.forename: Virginia E
authors.initials: VE
authors.lastname: Papaioannou
authors.forename: Akira
authors.initials: A
authors.lastname: Imamoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D001934:Branchial Region / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D002892:Chromosomes, Human, Pair 22; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004062:DiGeorge Syndrome / Q000378:metabolism*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D017353:Gene Deletion; D015870:Gene Expression / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D000072516:Retinoic Acid 4-Hydroxylase; D015398:Signal Transduction / Q000502:physiology*; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000378:metabolism*; D013950:Thymus Gland / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase