Neural precursor cells (NPCs) in the neocortex exhibit a high proliferation capacity during early embryonic development and give rise to cortical projection neurons after maturation.
Necdin, a mammal-specific MAGE (
melanoma antigen) family
protein that possesses anti-mitotic and pro-survival activities, is expressed abundantly in postmitotic neurons and moderately in tissue-specific stem cells or progenitors.
Necdin interacts with
E2F transcription factors and suppresses E2F1-dependent transcriptional activation of the
cyclin-dependent kinase Cdk1 gene. Here we show that
necdin serves as a suppressor of NPC proliferation in the embryonic neocortex.
Necdin is moderately expressed in the ventricular zone of mouse embryonic neocortex, in which proliferative cell populations are significantly increased in
necdin-null mice. In the neocortex of
necdin-null embryos, expression of Cdk1 and Sox2, a stem cell marker, is significantly increased, whereas expression of p16, a
cyclin-dependent kinase inhibitor, is markedly diminished. Cdk1 and p16 expression levels are also significantly increased and decreased, respectively, in primary NPCs prepared from
necdin-null embryos. Intriguingly,
necdin interacts directly with Bmi1, a
Polycomb group protein that suppresses p16 expression and promotes NPC proliferation. In HEK293A cells transfected with
luciferase reporter constructs,
necdin relieves Bmi1-dependent repression of p16 promoter activity, whereas Bmi1 counteracts
necdin-mediated repression of E2F1-dependent Cdk1 promoter activity. In lentivirus-infected primary NPCs,
necdin overexpression increases p16 expression, suppresses Cdk1 expression, and inhibits NPC proliferation, whereas Bmi1 overexpression suppresses p16 expression, increases Cdk1 expression, and promotes NPC proliferation. Our data suggest that embryonic NPC proliferation in the neocortex is regulated by the antagonistic interplay between
necdin and Bmi1.