Coordinated control of self-renewal and differentiation of neural stem cells by Myc and the p19ARF-p53 pathway.
The modes of proliferation and differentiation of neural stem cells (NSCs) are coordinately controlled during development, but the underlying mechanisms remain largely unknown. In this study, we show that the protooncoprotein Myc and the tumor suppressor p19(ARF) regulate both NSC self-renewal and their neuronal and glial fate in a developmental stage-dependent manner. Early-stage NSCs have low p19(ARF) expression and retain a high self-renewal and neurogenic capacity, whereas late-stage NSCs with higher p19(ARF) expression possess a lower self-renewal capacity and predominantly generate glia. Overexpression of Myc or inactivation of p19(ARF) reverts the properties of late-stage NSCs to those of early-stage cells. Conversely, inactivation of Myc or forced p19(ARF) expression attenuates self-renewal and induces precocious gliogenesis through modulation of the responsiveness to gliogenic signals. These actions of p19(ARF) in NSCs are mainly mediated by p53. We propose that opposing actions of Myc and the p19(ARF)-p53 pathway have important functions in coordinated developmental control of self-renewal and cell fate choices in NSCs.
Nagao
Motoshi
M
Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
Campbell
Kenneth
K
Burns
Kevin
K
Kuan
Chia-Yi
CY
Trumpp
Andreas
A
Nakafuku
Masato
M
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D051379:Mice; D008815:Mice, Inbred Strains; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D011247:Pregnancy; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53