The retinoblastoma protein, RB, is required for gastrointestinal endocrine cells to exit the cell cycle, but not for hormone expression.
Important functions of the RB family proteins include inhibition of cell cycle progression and regulation of terminal differentiation. We have examined the role of RB and the related protein, p107, in regulating cell cycle activity and differentiation of gastrointestinal endocrine cells, a relatively quiescent cell population, by conditionally disrupting the RB gene in neurogenin3 (Ngn3)-expressing cells in both p107(+/+) and p107(-/-) mice. Endocrine cells in the small intestine, colon, pancreas, and stomach were present in normal numbers in RB and RB-p107 mutants except for an increase in serotonin cells and decrease in ghrelin cells in the antral stomach. Deletion of RB resulted in a dramatic increase in proliferating serotonin cells in the antral stomach and intestine, whereas other enteroendocrine cell types exhibited much lower cell cycle activity or remained quiescent. The related p107 protein appears dispensable for enteroendocrine differentiation and does not functionally compensate for the loss of RB. Our results suggest that RB is required for enteroendocrine cells, particularly serotonin cells, to undergo cell cycle arrest as they terminally differentiate. RB has relatively subtle effects on enteroendocrine cell differentiation and is not required for the expression of the normal repertoire of hormones in the gastrointestinal tract.
Wang
Yang
Y
Division of Gastroenterology, GRASP Digestive Disease Center, Tufts-New England Medical Center, Boston, MA 02111, USA.
Ray
Subir K
SK
Hinds
Philip W
PW
Leiter
Andrew B
AB
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D019858:Enteroendocrine Cells / Q000166:cytology / Q000378:metabolism*; D005768:Gastrointestinal Hormones / Q000378:metabolism*; D041981:Gastrointestinal Tract / Q000166:cytology*; D054439:Ghrelin / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D005768:Gastrointestinal Hormones; D054439:Ghrelin; D009419:Nerve Tissue Proteins; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D012701:Serotonin; C407737:Neurog3 protein, mouse