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Thyroid Function in Mice with Compound Heterozygous and Homozygous Disruptions of SRC-1 and TIF-2 Coactivators: Evidence for Haploinsufficiency

Departments of Medicine (R.E.W., P.M.S., S.R.), Pathology (P.M.S.), Pediatrics (S.R.), and Committee on Genetics (S.R.), University of Chicago, Chicago, Illinois 60037; Institut de Génétique et de Biologie Moléculaire et Cellulaire CNRS (M.G., P.C.), INSERM, and Collège de France, 67404 Illkirch, C.U. de Strasbourg, France; and Department of Molecular and Cellular Biology (J.X., B.W.O.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Roy E. Weiss, University of Chicago, Thyroid Study Unit, MC 3090, 5841 South Maryland Avenue, Department of Medicine, Room M-376, Chicago, Illinois 60637-1470. E-mail: rweiss{at}medicine.bsd.uchicago.edu

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.

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