title: c-Myb is required for progenitor cell homeostasis in colonic crypts.
abstract: The colonic crypt is the functional unit of the colon mucosa with a central role in ion and water reabsorption. Under steady-state conditions, the distal colonic crypt harbors a single stem cell at its base that gives rise to highly proliferative progenitor cells that differentiate into columnar, goblet, and endocrine cells. The role of c-Myb in crypt homeostasis has not been elucidated. Here we have studied three genetically distinct hypomorphic c-myb mutant mouse strains, all of which show reduced colonic crypt size. The mutations target the key domains of the transcription factor: the DNA binding, transactivation, and negative regulatory domains. In vivo proliferation and cell cycle marker studies suggest that these mice have a progenitor cell proliferation defect mediated in part by reduced Cyclin E1 expression. To independently assess the extent to which c-myb is required for colonic crypt homeostasis we also generated a novel tissue-specific mouse model to allow the deletion of c-myb in adult colon, and using these mice we show that c-Myb is required for crypt integrity, normal differentiation, and steady-state proliferation.
authors.affiliation: Peter MacCallum Cancer Centre and Pathology Department, University of Melbourne, Melbourne VIC 8006, Australia.
authors.forename: Jordane
authors.initials: J
authors.lastname: Malaterre
authors.forename: Marina
authors.initials: M
authors.lastname: Carpinelli
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
authors.forename: Warren
authors.initials: W
authors.lastname: Alexander
authors.forename: Michael
authors.initials: M
authors.lastname: Cooke
authors.forename: Susan
authors.initials: S
authors.lastname: Sutton
authors.forename: Sebastian
authors.initials: S
authors.lastname: Dworkin
authors.forename: Joan K
authors.initials: JK
authors.lastname: Heath
authors.forename: Jon
authors.initials: J
authors.lastname: Frampton
authors.forename: Grant
authors.initials: G
authors.lastname: McArthur
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.forename: Douglas
authors.initials: D
authors.lastname: Hilton
authors.forename: Theo
authors.initials: T
authors.lastname: Mantamadiotis
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ramsay
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D003106:Colon / Q000378:metabolism*; D019927:Cyclin E / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015513:Oncogene Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C475820:CCNE1 protein, human; D019927:Cyclin E; D015513:Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D014157:Transcription Factors