Transcription factor foxq1 controls mucin gene expression and granule content in mouse stomach surface mucous cells.
OBJECTIVE
The gastric mucosa provides a stringent epithelial barrier and produces acid and enzymes that initiate digestion. In this regenerating tissue, progenitors differentiate continually into 4 principal specialized cell types, yet underlying mechanisms of differentiation are poorly understood. We identified stomach-restricted expression of the forkhead transcription factor FOXQ1.


METHODS
We used a combination of genetic, histochemical, ultrastructural, and molecular analysis to study gastric cell lineages with respect to FOXQ1.


RESULTS
Within the developing and adult gastrointestinal tract, Foxq1 messenger RNA (mRNA) is restricted to the stomach and expressed predominantly in foveolar (pit) cells, the abundant mucin-producing cells that line the mucosal surface. Mice carrying Foxq1 coding mutations show virtual absence of mRNA and protein for the backbone of the major stomach mucin MUC5AC. These observations correspond to a paucity of foveolar cell secretory vesicles and notable loss of stomach but not intestinal mucus. Transcriptional profiling identified a surprisingly restricted set of genes with altered expression in Foxq1 mutant stomachs. MUC5AC is a highly tissue-restricted product that similarly depends on FOXQ1 in its other major site of expression, conjunctival goblet cells.


CONCLUSIONS
Taken together, these observations imply that promotion of gastric MUC5AC synthesis is a primary, cell-autonomous function of FOXQ1. This study is the first to implicate a transcription factor in terminal differentiation of foveolar cells and begins to define the requirements to assemble highly specialized organelles and cells in the gastric mucosa.
Verzi
Michael P
MP
Dana-Farber Cancer Institute and Department of Medicine, Boston, Massachusetts, USA.
Khan
Abdul H
AH
Ito
Susumu
S
Shivdasani
Ramesh A
RA
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D019070:Cell Lineage; D003228:Conjunctiva / Q000166:cytology / Q000378:metabolism; D004847:Epithelial Cells / Q000000981:diagnostic imaging / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005753:Gastric Mucosa / Q000166:cytology / Q000000981:diagnostic imaging / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D055271:Mucin 5AC; D009077:Mucins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D012333:RNA, Messenger / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism*; D014158:Transcription, Genetic; D014463:Ultrasonography
D051858:Forkhead Transcription Factors; C107579:Foxq1 protein, mouse; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D009077:Mucins; D012333:RNA, Messenger