Embryonic retinoic acid synthesis is essential for early mouse post-implantation development

Nat Genet. 1999 Apr;21(4):444-8. doi: 10.1038/7788.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics
  • Aldehyde Oxidoreductases / genetics*
  • Aldehyde Oxidoreductases / metabolism*
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Embryo, Mammalian / abnormalities
  • Embryo, Mammalian / metabolism
  • Embryo, Mammalian / pathology
  • Embryonic Development / physiology*
  • Embryonic and Fetal Development / drug effects
  • Embryonic and Fetal Development / physiology*
  • Female
  • Fibroblast Growth Factor 10
  • Fibroblast Growth Factor 3
  • Fibroblast Growth Factor 8
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism
  • Gene Expression Regulation, Developmental*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Limb Buds / abnormalities
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Otx Transcription Factors
  • Pregnancy
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Response Elements
  • Retinal Dehydrogenase
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transgenes
  • Tretinoin / metabolism*
  • Tretinoin / pharmacology

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins
  • Fgf3 protein, mouse
  • Fgf8 protein, mouse
  • Fibroblast Growth Factor 10
  • Fibroblast Growth Factor 3
  • Hand1 protein, mouse
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • Otx Transcription Factors
  • Proto-Oncogene Proteins
  • Trans-Activators
  • Transcription Factors
  • helix-loop-helix protein, eHAND
  • homeobox A1 protein
  • Fibroblast Growth Factor 8
  • Tretinoin
  • Fibroblast Growth Factors
  • Aldehyde Oxidoreductases
  • Retinal Dehydrogenase