c-Myb is required for progenitor cell homeostasis in colonic crypts.
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.
Malaterre
Jordane
J
Peter MacCallum Cancer Centre and Pathology Department, University of Melbourne, Melbourne VIC 8006, Australia.
Carpinelli
Marina
M
Ernst
Matthias
M
Alexander
Warren
W
Cooke
Michael
M
Sutton
Susan
S
Dworkin
Sebastian
S
Heath
Joan K
JK
Frampton
Jon
J
McArthur
Grant
G
Clevers
Hans
H
Hilton
Douglas
D
Mantamadiotis
Theo
T
Ramsay
Robert G
RG
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
C475820:CCNE1 protein, human; D019927:Cyclin E; D015513:Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D014157:Transcription Factors