Foxa1 and Foxa2 control the differentiation of goblet and enteroendocrine L- and D-cells in mice

Gastroenterology. 2009 Dec;137(6):2052-62. doi: 10.1053/j.gastro.2009.08.059. Epub 2009 Sep 6.


Background & aims: The winged helix transcription factors Foxa1 and Foxa2 are expressed in all epithelia of the gastrointestinal tract from its embryonic origin into adulthood. In vitro studies have shown that Foxa1/a2 can transactivate the promoters of Mucin 2 (Muc2), which is expressed in goblet cells, and of preproglucagon, which is expressed in enteroendocrine cells. These findings suggest Foxa1/a2 as critical factors in the differentiation of gut epithelial cells.

Methods: Mice with intestine-specific simultaneous deletion of Foxa1 and Foxa2 were derived using the Cre-loxP system and analyzed using histologic and molecular means.

Results: Both Foxa1 and Foxa2 were deleted successfully in the epithelia of the small intestine and colon using Villin-Cre mice. Immunohistochemical staining showed that Foxa1/a2 mutants lack glucagon-like peptide-1- and peptide-2-expressing cells (L-cells), and have reduced numbers of somatostatin (D-cells) and peptide YY-expressing cells (L-cells). Preproglucagon, somatostatin, and peptide YY messenger RNA (mRNA) levels also were reduced significantly in Foxa1/a2 mutants. Thus, Foxa1 and Foxa2 are essential regulators of these enteroendocrine lineages in vivo. The mRNA levels of transcription factors Islet-1 and Pax6 were reduced significantly in the small intestine, showing that Foxa1 and Foxa2 impact on a transcription factor network in the enteroendocrine lineage. In addition, deletion of Foxa1/a2 caused a reduction in goblet cell number with altered expression of the secretory mucins Muc2, Mucin5b, Mucin5ac, and Mucin 6.

Conclusions: The winged helix factors Foxa1 and Foxa2 are essential members of the transcription factor network that govern secretory cell differentiation in the mammalian gastrointestinal tract.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation*
  • Enteroendocrine Cells / metabolism*
  • Enteroendocrine Cells / pathology
  • Eye Proteins / metabolism
  • Glucagon-Like Peptide 1 / metabolism
  • Glucagon-Like Peptide 2 / metabolism
  • Goblet Cells / metabolism*
  • Goblet Cells / pathology
  • Hepatocyte Nuclear Factor 3-alpha / deficiency
  • Hepatocyte Nuclear Factor 3-alpha / genetics
  • Hepatocyte Nuclear Factor 3-alpha / metabolism*
  • Hepatocyte Nuclear Factor 3-beta / deficiency
  • Hepatocyte Nuclear Factor 3-beta / genetics
  • Hepatocyte Nuclear Factor 3-beta / metabolism*
  • Homeodomain Proteins / metabolism
  • Immunohistochemistry
  • Intestine, Small / metabolism*
  • Intestine, Small / pathology
  • LIM-Homeodomain Proteins
  • Male
  • Mice
  • Mice, Knockout
  • Mucin 5AC / metabolism
  • Mucin-2 / metabolism
  • Mucin-5B / metabolism
  • PAX6 Transcription Factor
  • Paired Box Transcription Factors / metabolism
  • Peptide YY / metabolism
  • Proglucagon / metabolism
  • RNA, Messenger / metabolism
  • Repressor Proteins / metabolism
  • Somatostatin / metabolism
  • Somatostatin-Secreting Cells / metabolism*
  • Somatostatin-Secreting Cells / pathology
  • Transcription Factors


  • Eye Proteins
  • Foxa1 protein, mouse
  • Foxa2 protein, mouse
  • Glucagon-Like Peptide 2
  • Hepatocyte Nuclear Factor 3-alpha
  • Homeodomain Proteins
  • LIM-Homeodomain Proteins
  • Muc2 protein, mouse
  • Muc5ac protein, mouse
  • Muc5b protein, mouse
  • Mucin 5AC
  • Mucin-2
  • Mucin-5B
  • PAX6 Transcription Factor
  • Paired Box Transcription Factors
  • Pax6 protein, mouse
  • RNA, Messenger
  • Repressor Proteins
  • Transcription Factors
  • insulin gene enhancer binding protein Isl-1
  • Peptide YY
  • Hepatocyte Nuclear Factor 3-beta
  • Somatostatin
  • Proglucagon
  • Glucagon-Like Peptide 1