TGFβ2 regulates hypothalamic Trh expression through the TGFβ inducible early gene-1 (TIEG1) during fetal development

Mol Cell Endocrinol. 2015 Jan 15:400:129-39. doi: 10.1016/j.mce.2014.10.021. Epub 2014 Nov 18.

Abstract

The hypothalamus regulates the homeostasis of the organism by controlling hormone secretion from the pituitary. The molecular mechanisms that regulate the differentiation of the hypothalamic thyrotropin-releasing hormone (TRH) phenotype are poorly understood. We have previously shown that Klf10 or TGFβ inducible early gene-1 (TIEG1) is enriched in fetal hypothalamic TRH neurons. Here, we show that expression of TGFβ isoforms (1-3) and both TGFβ receptors (TβRI and II) occurs in the hypothalamus concomitantly with the establishment of TRH neurons during late embryonic development. TGFβ2 induces Trh expression via a TIEG1 dependent mechanism. TIEG1 regulates Trh expression through an evolutionary conserved GC rich sequence on the Trh promoter. Finally, in mice deficient in TIEG1, Trh expression is lower than in wild type animals at embryonic day 17. These results indicate that TGFβ signaling, through the upregulation of TIEG1, plays an important role in the establishment of Trh expression in the embryonic hypothalamus.

Keywords: Cell differentiation; Hypothalamus; Klf10; TGFβ; TIEG1; Trh.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics*
  • Embryo, Mammalian
  • Fetus
  • Gene Expression Regulation, Developmental*
  • Hypothalamus / cytology
  • Hypothalamus / growth & development
  • Hypothalamus / metabolism*
  • Immunohistochemistry
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / cytology
  • Neurons / metabolism*
  • Primary Cell Culture
  • Promoter Regions, Genetic
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Rats
  • Rats, Wistar
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction
  • Thyrotropin-Releasing Hormone / genetics
  • Thyrotropin-Releasing Hormone / metabolism*
  • Transcription Factors / deficiency
  • Transcription Factors / genetics*
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism
  • Transforming Growth Factor beta2 / genetics
  • Transforming Growth Factor beta2 / metabolism*
  • Transforming Growth Factor beta3 / genetics
  • Transforming Growth Factor beta3 / metabolism

Substances

  • DNA-Binding Proteins
  • Receptors, Transforming Growth Factor beta
  • Tieg1 protein, mouse
  • Transcription Factors
  • Transforming Growth Factor beta1
  • Transforming Growth Factor beta2
  • Transforming Growth Factor beta3
  • Thyrotropin-Releasing Hormone
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • Tgfbr1 protein, rat