Normal development and growth of mice carrying a targeted disruption of the alpha 1 retinoic acid receptor gene.
Three unlinked genes encode receptors for retinoic acid (RAR alpha, -beta, and -gamma). Each gene expresses two major protein isoforms differing in the amino terminal A domain by alternative promoter use, fused to common exons encoding most of the receptor protein. The two RAR alpha transcripts (RAR alpha 1 and -alpha 2) are differentially expressed and evolutionarily conserved, as are the RAR beta and -gamma transcripts, suggesting that each isoform may have specific functions in the development of animals. To address the biological function of the alpha 1 receptor, we have disrupted the portion of the RAR alpha gene encoding this isoform by homologous recombination in mouse embryonic stem cells. Surprisingly, offspring homozygous for this mutation were viable and showed no apparently altered phenotype. RNA analysis confirmed that the RAR alpha 1 transcript was absent in homozygous tissues, and no evidence for a compensatory increase of RAR alpha 2 or of another RAR gene was obtained to account for the vitality of the mutant animals. These results clearly demonstrate that loss of RAR alpha 1 function does not disrupt embryonic development and argue for combinatorial or overlapping functions among the RAR isoforms.
Li
E
E
Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge 02142.
Sucov
H M
HM
Lee
K F
KF
Evans
R M
RM
Jaenisch
R
R
D000818:Animals; D000954:Antigens, Surface / Q000032:analysis; D001853:Bone Marrow / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics*; D002460:Cell Line; D015342:DNA Probes; D004622:Embryo, Mammalian; D015698:Genomic Library; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006579:Heterozygote; D006720:Homozygote; D008099:Liver / Q000502:physiology; D008214:Lymphocytes / Q000502:physiology; D051379:Mice; D008811:Mice, Inbred DBA; D009132:Muscles / Q000502:physiology; D009928:Organ Specificity; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D018168:Receptors, Retinoic Acid; D015183:Restriction Mapping; D012879:Skin Physiological Phenomena; D013154:Spleen / Q000502:physiology; D013950:Thymus Gland / Q000502:physiology; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism
D000954:Antigens, Surface; D002352:Carrier Proteins; D015342:DNA Probes; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D012313:RNA