A retinoic acid-inducible transgenic marker of sino-atrial development in the mouse heart.
To study the specification of inflow structures in the heart we generated transgenic animals harboring the human alkaline phosphatase (HAP) gene driven by the proximal 840 bp of a quail SMyHC3 promoter. In transgenic mice, the SMyHC3-HAP reporter was expressed in posterior heart precursors at 8.25 dpc, in sinus venosa and in the atrium at 8.5 and 9.0 dpc, and in the atria from 10.5 dpc onwards. SMyHC3-HAP transgene expression overlapped synthesis and endogenous response to retinoic acid (RA) in the heart, as determined by antibodies directed against a key RA synthetic enzyme and by staining of RAREhsplacZ transgenic animals. A single pulse of all-trans RA administered to pregnant mice at 7.5, but not after 8.5, dpc induced cardiac dismorphology, ranging from complete absence of outflow tract and ventricles to hearts with reduced ventricles expressing both SMyHC3-HAP and ventricular markers. Blockade of RA synthesis with disulfiram inhibited RA-induced transcription and produced hearts lacking the atrial chamber. This study defines a novel marker for atrial-restricted transcription in the developing mouse heart. It also suggests that atrial-specific gene expression is controlled by localized synthesis of RA, and that exclusion of RA from ventricular precursors is essential for correct specification of the ventricles.
Xavier-Neto
J
J
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Neville
C M
CM
Shapiro
M D
MD
Houghton
L
L
Wang
G F
GF
Nikovits
W
W
Stockdale
F E
FE
Rosenthal
N
N
D000469:Alkaline Phosphatase / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D004221:Disulfiram / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005819:Genetic Markers; D006321:Heart / Q000196:embryology*; D006325:Heart Atria / Q000196:embryology / Q000378:metabolism; D006330:Heart Defects, Congenital / Q000139:chemically induced* / Q000235:genetics; D006352:Heart Ventricles / Q000196:embryology / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D020218:Response Elements; D015398:Signal Transduction; D014158:Transcription, Genetic; D019076:Transgenes; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D005819:Genetic Markers; D014212:Tretinoin; D000469:Alkaline Phosphatase; D004221:Disulfiram