Disrupted blastocoele formation reveals a critical developmental role for long-chain acyl-CoA dehydrogenase.
Long-chain acyl-CoA dehydrogenase (LCAD) deficiency has not been found in human patients. There has been an LCAD deficient (LCAD-/-) mouse model developed via gene targeting strategies that has gestational loss as a part of its phenotype. We tested the hypothesis that LCAD deficiency disrupts normal embryonic development and explains at least in part the gestational loss in the mouse and may suggest a mechanism to explain the lack of any human patients with this inherited enzyme deficiency. We cultured and evaluated embryos with three different genotypes: LCAD+/+, LCAD+/-, and LCAD-/-. We found a significantly increased rate of death (P<0.012) in LCAD-/- embryos at the morula-to-blastocyst conversion indicating a deficient ability to complete the development of a blastocoele and formation of a blastocyst. Furthermore, we hypothesized that we could rescue LCAD-/- embryos in culture by supplying excess fatty acids of chain-lengths that could be readily oxidized by them despite their inherited enzyme deficiency. We were unable, however, to demonstrate any rescue by supplementing the culture medium with fatty acids of a wide-range of chain-lengths. Therefore, overall we demonstrated a severely deficient capacity for LCAD-/- embryos to develop past the morula stage with intermediate rates of development found in the LCAD+/- embryos as compared to the LCAD+/+ embryos. Furthermore, we were unable to rescue the LCAD-/- embryos with any fatty acid supplementation.
Berger
Paul S
PS
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
Wood
Philip A
PA
D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001755:Blastocyst / Q000187:drug effects / Q000201:enzymology*; D047108:Embryonic Development / Q000187:drug effects / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D051379:Mice; D008817:Mice, Mutant Strains
D005227:Fatty Acids; D044942:Acyl-CoA Dehydrogenase, Long-Chain