Thyroid function in mice with compound heterozygous and homozygous disruptions of SRC-1 and TIF-2 coactivators: evidence for haploinsufficiency.
Steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF)-2 are homologous nuclear receptor coactivators. We have investigated their possible redundancy as thyroid hormone (TH) coactivators by measuring thyroid function in compound SRC-1 and TIF-2 knock out (KO) mice. Whereas SRC-1 KO (SRC-1(-/-)) mice are resistant to TH and SRC-1(+/-) are not, we now demonstrate that TIF-2 KO (TIF-2(-/-)) mice have normal thyroid function. Yet double heterozygous, SRC-1(+/-)/TIF-2(+/-) mice manifested resistance to TH of a similar degree as that in mice completely deficient in SRC-1. KO of both SRC-1 and TIF-2 resulted in marked increases of serum TH and thyrotropin concentrations. This work demonstrates gene dosage effect in nuclear coactivators manifesting as haploinsufficiency and functional redundancy of SRC-1 and TIF-2.
Weiss
Roy E
RE
Department of Medicine, University of Chicago, Chicago, Illinois 60037, USA. rweiss@medicine.bsd.uchicago.edu
Gehin
Martine
M
Xu
Jianming
J
Sadow
Peter M
PM
O'Malley
Bert W
BW
Chambon
Pierre
P
Refetoff
Samuel
S
D000818:Animals; D018628:Gene Dosage; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D051548:Histone Acetyltransferases; D006720:Homozygote; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D013960:Thyroid Function Tests; D013961:Thyroid Gland / Q000502:physiology*; D013963:Thyroid Hormones / Q000502:physiology; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics*; D014284:Triiodothyronine / Q000097:blood / Q000502:physiology
C498002:Ncoa2 protein, mouse; D051958:Nuclear Receptor Coactivator 2; D013963:Thyroid Hormones; D014157:Transcription Factors; D014284:Triiodothyronine; D013972:Thyrotropin; D051548:Histone Acetyltransferases; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1; D013974:Thyroxine