Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice.
The Polycomb group (PcG) gene Bmi1 promotes cell proliferation and stem cell self-renewal by repressing the Ink4a/Arf locus. We used a genetic approach to investigate whether Ink4a or Arf is more critical for relaying Bmi1 function in lymphoid cells, neural progenitors, and neural stem cells. We show that Arf is a general target of Bmi1, however particularly in neural stem cells, derepression of Ink4a contributes to Bmi1(-/-) phenotypes. Additionally, we demonstrate haploinsufficient effects for the Ink4a/Arf locus downstream of Bmi1 in vivo. This suggests differential, cell type-specific roles for Ink4a versus Arf in PcG-mediated (stem) cell cycle control.
Bruggeman
Sophia W M
SW
Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Valk-Lingbeek
Merel E
ME
van der Stoop
Petra P M
PP
Jacobs
Jacqueline J L
JJ
Kieboom
Karin
K
Tanger
Ellen
E
Hulsman
Danielle
D
Leung
Carly
C
Arsenijevic
Yvan
Y
Marino
Silvia
S
van Lohuizen
Maarten
M
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D016922:Cellular Senescence; D002531:Cerebellum / Q000166:cytology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000378:metabolism; D019942:Genes, p16; D006579:Heterozygote; D008221:Lymphoid Tissue / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
C489421:Bmi1 protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D025803:Tumor Suppressor Protein p14ARF; D063150:Polycomb Repressive Complex 1