The integrity of the FOG-2 LXCXE pRb-binding motif is required for small intestine homeostasis

Exp Physiol. 2019 Jul;104(7):1074-1089. doi: 10.1113/EP087369. Epub 2019 May 14.

Abstract

New findings: What is the central question of this study? Do Fog2Rb- / Rb- mice present a defect of small intestine homeostasis? What is the main finding and its importance? The importance of interactions between FOG-2 and pRb in adipose tissue physiology has previously been demonstrated. Here it is shown that this interaction is also intrinsic to small intestine homeostasis and exerts extrinsic control over mouse metabolism. Thus, this association is involved in maintaining small intestine morphology, and regulating crypt proliferation and lineage differentiation. It therefore affects mouse growth and adaptation to a high-fat diet.

Abstract: GATA transcription factors and their FOG cofactors play a key role in tissue-specific development and differentiation, from worms to humans. We have shown that GATA-1 and FOG-2 contain an LXCXE pRb-binding motif. Interactions between retinoblastoma protein (pRb) and GATA-1 are crucial for erythroid proliferation and differentiation, whereas the LXCXE pRb-binding site of FOG-2 is involved in adipogenesis. Fog2-knock-in mice have defective pRb binding and are resistant to obesity, due to efficient white-into-brown fat conversion. Our aim was to investigate the pathophysiological impact of FOG-2-pRb interaction on the small intestine and mouse growth. Histological analysis of the small intestine revealed architectural changes in Fog2Rb- / Rb- mice, including villus shortening, with crypt expansion and a change in muscularis propria thickness. These differences were more marked in the proximo-distal part of the small intestine and were associated with an increase in crypt cell proliferation and disruption of the goblet and Paneth cell lineage. The small intestine of the mutants was unable to adapt to a high-fat diet, and had significantly lower plasma lipid levels on such a diet. Fog2Rb- / Rb- mice displayed higher levels of glucose-dependent insulinotropic peptide release, and lower levels of insulin-like growth factor I release on a regular diet. Their intestinal lipid absorption was impaired, resulting in restricted weight gain. In addition to the intrinsic effects of the mutation on adipose tissue, we show here an extrinsic relationship between the intestine and the effect of FOG-2 mutation on mouse metabolism. In conclusion, the interaction of FOG-2 with pRb coordinates the crypt-villus axis and controls small intestine homeostasis.

Keywords: FOG-2; crypt cell proliferation; morphological adaptation; retinoblastoma; small intestine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Diet, High-Fat / adverse effects*
  • Female
  • Homeostasis / physiology*
  • Intestine, Small / cytology
  • Intestine, Small / metabolism*
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Transgenic
  • Proline-Rich Protein Domains / physiology*
  • Protein Binding / physiology
  • Random Allocation
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • DNA-Binding Proteins
  • Transcription Factors
  • Zfpm2 protein, mouse