Cdk2 is critical for proliferation and self-renewal of neural progenitor cells in the adult subventricular zone.
We investigated the function of cyclin-dependent kinase 2 (Cdk2) in neural progenitor cells during postnatal development. Chondroitin sulfate proteoglycan (NG2)-expressing progenitor cells of the subventricular zone (SVZ) show no significant difference in density and proliferation between Cdk2(-/-) and wild-type mice at perinatal ages and are reduced only in adult Cdk2(-/-) mice. Adult Cdk2(-/-) SVZ cells in culture display decreased self-renewal capacity and enhanced differentiation. Compensatory mechanisms in perinatal Cdk2(-/-) SVZ cells, which persist until postnatal day 15, involve increased Cdk4 expression that results in retinoblastoma protein inactivation. A subsequent decline in Cdk4 activity to wild-type levels in postnatal day 28 Cdk2(-/-) cells coincides with lower NG2+ proliferation and self-renewal capacity similar to adult levels. Cdk4 silencing in perinatal Cdk2(-/-) SVZ cells abolishes Cdk4 up-regulation and reduces cell proliferation and self- renewal to adult levels. Conversely, Cdk4 overexpression in adult SVZ cells restores proliferative capacity to wild-type levels. Thus, although Cdk2 is functionally redundant in perinatal SVZ, it is important for adult progenitor cell proliferation and self-renewal through age-dependent regulation of Cdk4.
Jablonska
Beata
B
Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, USA.
Aguirre
Adan
A
Vandenbosch
Renaud
R
Belachew
Shibeshih
S
Berthet
Cyril
C
Kaldis
Philipp
P
Gallo
Vittorio
V
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D019070:Cell Lineage; D049109:Cell Proliferation; D002552:Cerebral Ventricles / Q000166:cytology* / Q000378:metabolism; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000502:physiology*; D051358:Cyclin-Dependent Kinase 4 / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D009474:Neurons / Q000166:cytology*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
D018797:Cell Cycle Proteins; D011508:Chondroitin Sulfate Proteoglycans; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4