Loss of retinoic acid receptor gamma function in F9 cells by gene disruption results in aberrant Hoxa-1 expression and differentiation upon retinoic acid treatment.
Retinoic acid (RA) signal transduction is believed to be mediated through several high-affinity nuclear receptors [RA receptors (RARs) and retinoid X receptors], which are members of the steroid/thyroid/vitamin D superfamily and function as transcription factors. Why multiple RARs exist and what gene targets are regulated by each of the three receptors remain compelling questions in developmental biology. Through targeted disruption of both RAR gamma alleles, we have identified several differentiation-specific genes that are regulated either directly or indirectly by RAR gamma in F9 embryonal carcinoma cells. These include genes encoding Hoxa-1 (Hox-1.6) and the extracellular matrix proteins laminin B1 and collagen type IV (alpha 1), all of which are RA inducible in wild-type F9 embryonal carcinoma cells but are not significantly induced in the RAR gamma-/- lines. In contrast, transcripts encoding Hoxb-1 (Hox-2.9) and cellular RA binding protein II (CRABPII) are activated by RA for a longer period of time in the RAR gamma-/- lines compared to the wild-type F9 line. Not all RA-responsive genes are aberrantly expressed; Rex-1, RAR beta, and SPARC transcripts are regulated in the RAR gamma-/- lines as they are in F9 wild-type cells. Our results support the idea that each RAR may regulate different subsets of RA-responsive genes, which may explain, in part, the complex regulation of developmental processes by retinoids.
Boylan
J F
JF
Department of Pharmacology, Cornell University Medical College, New York, NY 10021.
Lohnes
D
D
Taneja
R
R
Chambon
P
P
Gudas
L J
LJ
D000818:Animals; D018236:Carcinoma, Embryonal / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D005786:Gene Expression Regulation; D005801:Genes, Homeobox; D066298:In Vitro Techniques; D051379:Mice; D016254:Mutagenesis, Insertional; D012333:RNA, Messenger / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D014212:Tretinoin