Lack of the cell-cycle inhibitor p27Kip1 results in selective increase of transit-amplifying cells for adult neurogenesis.
The subventricular zone (SVZ) is the largest germinal layer in the adult mammalian brain and comprises stem cells, transit-amplifying progenitors, and committed neuroblasts. Although the SVZ contains the highest concentration of dividing cells in the adult brain, the intracellular mechanisms controlling their proliferation have not been elucidated. We show here that loss of the cyclin-dependent kinase inhibitor p27Kip1 has very specific effects on a population of CNS progenitors responsible for adult neurogenesis. Using bromodeoxyuridine and [(3)H]thymidine incorporation to label cells in S phase and cell-specific markers and electron microscopy to identify distinct cell types, we compared the SVZ structure and proliferation characteristics of wild-type and p27Kip1-null mice. Loss of p27Kip1 had no effect on the number of stem cells but selectively increased the number of the transit-amplifying progenitors concomitantly with a reduction in the number of neuroblasts. We conclude that cell-cycle regulation of SVZ adult progenitors is remarkably cell-type specific, with p27Kip1 being a key regulator of the cell division of the transit-amplifying progenitors.
Doetsch
Fiona
F
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Verdugo
Jose Manuel-Garcia
JM
Caille
Isabelle
I
Alvarez-Buylla
Arturo
A
Chao
Moses V
MV
Casaccia-Bonnefil
Patrizia
P
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D020547:Lateral Ventricles / Q000166:cytology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D018874:Spheroids, Cellular / Q000166:cytology; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D013936:Thymidine / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D001973:Bromodeoxyuridine; D013936:Thymidine