Embryonic retinoic acid synthesis is essential for early mouse post-implantation development.
A number of studies have suggested that the active derivative of vitamin A, retinoic acid (RA), may be important for early development of mammalian embryos. Severe vitamin A deprivation in rodents results in maternal infertility, precluding a thorough investigation of the role of RA during embryogenesis. Here we show that production of RA by the retinaldehyde dehydrogenase-2 (Raldh2) enzyme is required for mouse embryo survival and early morphogenesis. Raldh2 is an NAD-dependent aldehyde dehydrogenase with high substrate specificity for retinaldehyde. Its pattern of expression during mouse development has suggested that it may be responsible for embryonic RA synthesis. We generated a targeted disruption of the mouse Raldh2 gene and found that Raldh2-/- embryos, which die at midgestation without undergoing axial rotation (body turning), exhibit shortening along the anterioposterior axis and do not form limb buds. Their heart consists of a single, medial, dilated cavity. Their frontonasal region is truncated and their otocysts are severely reduced. These defects result from a block in embryonic RA synthesis, as shown by the lack of activity of RA-responsive transgenes, the altered expression of an RA-target homeobox gene and the near full rescue of the mutant phenotype by maternal RA administration. Our data establish that RA synthesized by the post-implantation mammalian embryo is an essential developmental hormone whose lack leads to early embryo death.
Niederreither
K
K
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP/Collège de France, Illkirch, C.U. de Strasbourg, France.
Subbarayan
V
V
Dollé
P
P
Chambon
P
P
D000015:Abnormalities, Multiple / Q000235:genetics; D000445:Aldehyde Oxidoreductases / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D047108:Embryonic Development / Q000502:physiology*; D005314:Embryonic and Fetal Development / Q000187:drug effects / Q000502:physiology*; D005260:Female; D051526:Fibroblast Growth Factor 10; D051518:Fibroblast Growth Factor 3; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D018878:Limb Buds / Q000002:abnormalities; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D051857:Otx Transcription Factors; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D050697:Retinal Dehydrogenase; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D019076:Transgenes; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D000099261:Homeobox A1 Protein
D000445:Aldehyde Oxidoreductases; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D051526:Fibroblast Growth Factor 10; D051518:Fibroblast Growth Factor 3; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D051857:Otx Transcription Factors; D011518:Proto-Oncogene Proteins; D050697:Retinal Dehydrogenase; D015534:Trans-Activators; D014157:Transcription Factors; D014212:Tretinoin; D000099261:Homeobox A1 Protein; C489197:Fgf3 protein, mouse; C496457:Fgf8 protein, mouse; C095572:Hand1 protein, mouse; C097341:helix-loop-helix protein, eHAND