SAM pointed domain ETS factor (SPDEF) regulates terminal differentiation and maturation of intestinal goblet cells.
OBJECTIVE
SPDEF (also termed PDEF or PSE) is an ETS family transcription factor that regulates gene expression in the prostate and goblet cell hyperplasia in the lung. Spdef has been reported to be expressed in the intestine. In this paper, we identify an important role for Spdef in regulating intestinal epithelial cell homeostasis and differentiation.


METHODS
SPDEF expression was inhibited in colon cancer cells to determine its ability to control goblet cell gene activation. The effects of transgenic expression of Spdef on intestinal differentiation and homeostasis were determined.


RESULTS
In LS174T colon cancer cells treated with Notch/gamma-secretase inhibitor to activate goblet cell gene expression, shRNAs that inhibited SPDEF also repressed expression of goblet cell genes AGR2, MUC2, RETLNB, and SPINK4. Transgenic expression of Spdef caused the expansion of intestinal goblet cells and corresponding reduction in Paneth, enteroendocrine, and absorptive enterocytes. Spdef inhibited proliferation of intestinal crypt cells without induction of apoptosis. Prolonged expression of the Spdef transgene caused a progressive reduction in the number of crypts that expressed Spdef, consistent with its inhibitory effects on cell proliferation.


CONCLUSIONS
Spdef was sufficient to inhibit proliferation of intestinal progenitors and induce differentiation into goblet cells; SPDEF was required for activation of goblet cell associated genes in vitro. These data support a model in which Spdef promotes terminal differentiation into goblet cells of a common goblet/Paneth progenitor.
Noah
Taeko K
TK
Division of Gastroenterology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Kazanjian
Avedis
A
Whitsett
Jeffrey
J
Shroyer
Noah F
NF
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020397:Goblet Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D009928:Organ Specificity / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D019076:Transgenes / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D004318:Doxycycline; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; C500943:Atoh1 protein, mouse; C079873:Gfi1 protein, mouse; C403974:SPDEF protein, human; C519908:Spdef protein, mouse