Transcriptional factor aryl hydrocarbon receptor (Ahr) controls cardiovascular and respiratory functions by regulating the expression of the Vav3 proto-oncogene.
Aryl hydrocarbon receptor (Ahr) is a transcriptional factor involved in detoxification responses to pollutants and in intrinsic biological processes of multicellular organisms. We recently described that Vav3, an activator of Rho/Rac GTPases, is an Ahr transcriptional target in embryonic fibroblasts. These results prompted us to compare the Ahr(-/-) and Vav3(-/-) mouse phenotypes to investigate the implications of this functional interaction in vivo. Here, we show that Ahr is important for Vav3 expression in kidney, lung, heart, liver, and brainstem regions. This process is not affected by the administration of potent Ahr ligands such as benzo[a]pyrene. We also report that Ahr- and Vav3-deficient mice display hypertension, tachypnea, and sympathoexcitation. The Ahr gene deficiency also induces the GABAergic transmission defects present in the Vav3(-/-) ventrolateral medulla, a main cardiorespiratory brainstem center. However, Ahr(-/-) mice, unlike Vav3-deficient animals, display additional defects in fertility, perinatal growth, liver size and function, closure, spleen size, and peripheral lymphocytes. These results demonstrate that Vav3 is a bona fide Ahr target that is in charge of a limited subset of the developmental and physiological functions controlled by this transcriptional factor. Our data also reveal the presence of sympathoexcitation and new cardiorespiratory defects in Ahr(-/-) mice.
Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas-Salamanca University, 37007 Salamanca, Spain.
Vincent
V
Sauzeau
José M
JM
Carvajal-González
Adelaida S
AS
Riolobos
María A
MA
Sevilla
Mauricio
M
Menacho-Márquez
Angel C
AC
Román
Antonio
A
Abad
María J
MJ
Montero
Pedro
P
Fernández-Salguero
Xosé R
XR
Bustelo
D000818:Animals; D001564:Benzo(a)pyrene / Q000494:pharmacology; D001933:Brain Stem / Q000378:metabolism; D002319:Cardiovascular System / Q000378:metabolism*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006973:Hypertension / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity / Q000187:drug effects / Q000502:physiology; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D012137:Respiratory System / Q000378:metabolism*; D012893:Sleep Wake Disorders / Q000235:genetics / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
D051567:Proto-Oncogene Proteins c-vav; D018336:Receptors, Aryl Hydrocarbon; C496622:Vav3 protein, mouse; D001564:Benzo(a)pyrene; D020744:rac GTP-Binding Proteins