Thyroid function in mice with compound heterozygous and homozygous disruptions of SRC-1 and TIF-2 coactivators:

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Roy E Weiss1, Martine Gehin, Jianming Xu

  • 1Department of Medicine, University of Chicago, Chicago, Illinois 60037, USA. rweiss@medicine.bsd.uchicago.edu

Endocrinology
|March 19, 2002
PubMed

Insights

Steroid receptor coactivator-1 (SRC-1) and transcriptional intermediary factor-2 (TIF-2) show functional redundancy in thyroid hormone (TH) regulation. Gene dosage effects and haploinsufficiency were observed in knockout mice.

Area of Science:

  • Molecular Endocrinology
  • Nuclear Receptor Signaling
  • Genetics and Genomics

Background:

  • Steroid receptor coactivator-1 (SRC-1) and transcriptional intermediary factor-2 (TIF-2) are homologous nuclear receptor coactivators.
  • Their potential functional redundancy in thyroid hormone (TH) coactivation requires investigation.

Purpose of the Study:

  • To investigate the functional redundancy of SRC-1 and TIF-2 as thyroid hormone coactivators.
  • To determine the effects of combined SRC-1 and TIF-2 knockout on thyroid function.

Main Methods:

  • Generation and analysis of SRC-1 and TIF-2 knockout (KO) mouse models.
  • Measurement of thyroid function, including serum TH and thyrotropin levels, in various KO genotypes (SRC-1(-/-), TIF-2(-/-), SRC-1(+/-)/TIF-2(+/-), and double KO).
  • Assessment of TH resistance in different genetic backgrounds.

Main Results:

  • SRC-1 knockout (SRC-1(-/-)) mice exhibit resistance to thyroid hormone (TH).
  • TIF-2 knockout (TIF-2(-/-)) mice display normal thyroid function.
  • Double heterozygous SRC-1(+/-)/TIF-2(+/-) mice show TH resistance comparable to SRC-1(-/-) mice, indicating haploinsufficiency.
  • Complete knockout of both SRC-1 and TIF-2 leads to significantly elevated serum TH and thyrotropin concentrations.

Conclusions:

  • SRC-1 and TIF-2 exhibit functional redundancy as thyroid hormone coactivators.
  • This study demonstrates a gene dosage effect in nuclear coactivators.
  • Haploinsufficiency of SRC-1 and TIF-2 contributes to altered thyroid hormone regulation.

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