Th-POK regulates mammary gland lactation through mTOR-SREBP pathway

PLoS Genet. 2018 Feb 8;14(2):e1007211. doi: 10.1371/journal.pgen.1007211. eCollection 2018 Feb.

Abstract

The Th-inducing POK (Th-POK, also known as ZBTB7B or cKrox) transcription factor is a key regulator of lineage commitment of immature T cell precursors. It is yet unclear the physiological functions of Th-POK besides helper T cell differentiation. Here we show that Th-POK is restrictedly expressed in the luminal epithelial cells in the mammary glands that is upregulated at late pregnancy and lactation. Lineage restrictedly expressed Th-POK exerts distinct biological functions in the mammary epithelial cells and T cells in a tissue-specific manner. Th-POK is not required for mammary epithelial cell fate determination. Mammary gland morphogenesis in puberty and alveologenesis in pregnancy are phenotypically normal in the Th-POK-deficient mice. However, Th-POK-deficient mice are defective in triggering the onset of lactation upon parturition with large cellular lipid droplets retained within alveolar epithelial cells. As a result, Th-POK knockout mice are unable to efficiently secret milk lipid and to nurse the offspring. Such defect is mainly attributed to the malfunctioned mammary epithelial cells, but not the tissue microenvironment in the Th-POK deficient mice. Th-POK directly regulates expression of insulin receptor substrate-1 (IRS-1) and insulin-induced Akt-mTOR-SREBP signaling. Th-POK deficiency compromises IRS-1 expression and Akt-mTOR-SREBP signaling in the lactating mammary glands. Conversely, insulin induces Th-POK expression. Thus, Th-POK functions as an important feed-forward regulator of insulin signaling in mammary gland lactation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Epithelial Cells / physiology
  • Female
  • Insulin / metabolism
  • Lactation / genetics*
  • Male
  • Mammary Glands, Animal / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pregnancy
  • Signal Transduction / genetics
  • Sterol Regulatory Element Binding Proteins / metabolism*
  • TOR Serine-Threonine Kinases / metabolism*
  • Transcription Factors / physiology*

Substances

  • Insulin
  • Sterol Regulatory Element Binding Proteins
  • Th-POK protein, mouse
  • Transcription Factors
  • TOR Serine-Threonine Kinases

Grants and funding

The work was supported by the National Natural Science Foundation of China (81430067, 31371408 and 31190061), Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12010100), and the CAS/SAFEA International Partnership Program for Creative Research Teams. GG is a scholar of the SA-SIBS Scholarship Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.