A role of endogenous histone acetyltransferase steroid hormone receptor coactivator (SRC) 3 in thyroid hormone signaling during Xenopus intestinal metamorphosis.

BACKGROUND Thyroid hormone (T3) plays an important role in regulating vertebrate developmental, cellular and metabolic processes via T3 receptor (TR). Liganded TR recruit coactivator complexes that include steroid receptor coactivators (SRC1, SRC2 or SRC3), which are histone acetyltransferases, to T3 responsive promoters. The functions of endogenous coactivators during T3-dependent mammalian adult organ development remain largely unclear in part due to the difficulty to access and manipulate late stage embryos and neonates. We use Xenopus metamorphosis as a model for postembryonic development in vertebrates. This process is controlled by T3 and involves drastic changes in every organ/tissue and can be easily manipulated. We have previously found that SRC3 was upregulated in the intestine during amphibian metamorphosis. METHODS To determine the function of endogenous SRC3 during intestinal remodeling, we have generated Xenopus tropicalis animals lacking a functional SRC3 gene and analyzed the resulting phenotype. RESULTS While removing SRC3 had no apparent effect on external development and animal gross morphology, the SRC3 (-/-) tadpoles displayed a reduction in the acetylation of histone H4 in the intestine comparing to that in wild type animals. Furthermore, the expression of TR target genes was also reduced in SRC3 (-/-) tadpoles during intestinal remodeling. Importantly, SRC3 (-/-) tadpoles had inhibited/delayed intestinal remodeling during natural and T3-induced metamorphosis, including reduced adult intestinal stem cell proliferation and apoptosis of larval epithelial cells. CONCLUSION Our results thus demonstrate that SRC3 is a critical component of the TR-signaling pathway in vivo during intestinal remodeling.