Retinoic acid deficiency alters second heart field formation.
Retinoic acid (RA), the active derivative of vitamin A, has been implicated in various steps of cardiovascular development. The retinaldehyde dehydrogenase 2 (RALDH2) enzyme catalyzes the second oxidative step in RA biosynthesis and its loss of function creates a severe embryonic RA deficiency. Raldh2(-/-) knockout embryos fail to undergo heart looping and have impaired atrial and sinus venosus development. To understand the mechanism(s) producing these changes, we examined the contribution of the second heart field (SHF) to pharyngeal mesoderm, atria, and outflow tract in Raldh2(-/-) embryos. RA deficiency alters SHF gene expression in two ways. First, Raldh2(-/-) embryos exhibited a posterior expansion of anterior markers of the SHF, including Tbx1, Fgf8, and the Mlc1v-nlacZ-24/Fgf10 reporter transgene as well as of Islet1. This occurred at early somite stages, when cardiac defects became irreversible in an avian vitamin A-deficiency model, indicating that endogenous RA is required to restrict the SHF posteriorly. Explant studies showed that this expanded progenitor population cannot differentiate properly. Second, RA up-regulated cardiac Bmp expression levels at the looping stage. The contribution of the SHF to both inflow and outflow poles was perturbed under RA deficiency, creating a disorganization of the heart tube. We also investigated genetic cross-talk between Nkx2.5 and RA signaling by generating double mutant mice. Strikingly, Nkx2.5 deficiency was able to rescue molecular defects in the posterior region of the Raldh2(-/-) mutant heart, in a gene dosage-dependent manner.
Ryckebusch
Lucile
L
Developmental Biology Institute of Marseille-Luminy, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6216, Campus de Luminy Case 907, 13009 Marseille, France.
Wang
Zengxin
Z
Bertrand
Nicolas
N
Lin
Song-Chang
SC
Chi
Xuan
X
Schwartz
Robert
R
Zaffran
Stéphane
S
Niederreither
Karen
K
D000445:Aldehyde Oxidoreductases / Q000235:genetics*; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006321:Heart / Q000196:embryology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics; D014212:Tretinoin / Q000378:metabolism*
D019485:Bone Morphogenetic Proteins; D014212:Tretinoin; D000445:Aldehyde Oxidoreductases; C470579:RALDH2 protein, mouse