title: Endothelial neuropilin disruption in mice causes DiGeorge syndrome-like malformations via mechanisms distinct to those caused by loss of Tbx1.
abstract: The spectrum of human congenital malformations known as DiGeorge syndrome (DGS) is replicated in mice by mutation of Tbx1. Vegfa has been proposed as a modifier of DGS, based in part on the occurrence of comparable phenotypes in Tbx1 and Vegfa mutant mice. Many additional genes have been shown to cause DGS-like phenotypes in mice when mutated; these generally intersect in some manner with Tbx1, and therefore impact the same developmental processes in which Tbx1 itself is involved. In this study, using Tie2Cre, we show that endothelial-specific mutation of the gene encoding the VEGFA coreceptor neuropilin-1 (Nrp1) also replicates the most prominent terminal phenotypes that typify DGS. However, the developmental etiologies of these defects are fundamentally different from those caused by absence of TBX1. In Tie2Cre/Nrp1 mutants, initial pharyngeal organization is normal but subsequent pharyngeal organ growth is impaired, second heart field differentiation is normal but cardiac outflow tract cushion organization is distorted, neural crest cell migration is normal, and palatal mesenchyme proliferation is impaired with no change in apoptosis. Our results demonstrate that impairment of VEGF-dependent endothelial pathways leads to a spectrum of DiGeorge syndrome-type malformations, through processes that are distinguishable from those controlled by Tbx1.
authors.affiliation: Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California Keck School of Medicine, Los Angeles, California, United States of America.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhou
authors.forename: Mohammad
authors.initials: M
authors.lastname: Pashmforoush
authors.forename: Henry M
authors.initials: HM
authors.lastname: Sucov
mesh_terms: D000818:Animals; D017209:Apoptosis; D002465:Cell Movement; D049109:Cell Proliferation; D004062:DiGeorge Syndrome / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004727:Endothelium / Q000378:metabolism*; D017353:Gene Deletion; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009024:Morphogenesis; D009154:Mutation; D009432:Neural Crest / Q000166:cytology; D039921:Neuropilins / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D042787:Receptor, TIE-2
chemical_list: D039921:Neuropilins; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse