Zac1 Regulates Cell Cycle Arrest in Neuronal Progenitors via Tcf4

Abstract

ABSTRACT Imprinted genes play a critical role in brain development and mental health, although the underlying molecular and cellular mechanisms remain incompletely understood. The family of basic helix-loop-helix (bHLH) proteins directs the proliferation, differentiation, and specification of distinct neuronal progenitor populations. Here, we identified the bHLH factor gene Tcf4 as a direct target gene of Zac1/Plagl1, a maternally imprinted transcriptional regulator, during early neurogenesis. Zac1 and Tcf4 expression levels concomitantly increased during neuronal progenitor differentiation; moreover, Zac1 interacts with two cis -regulatory elements in the Tcf4 gene locus, and these elements together confer synergistic activation of the Tcf4 gene. Tcf4 upregulation enhances the expression of the cyclin-dependent kinase inhibitor gene p57 Kip2 , a paternally imprinted Tcf4 target gene, and increases the number of cells in G 1 phase. Overall, we show that Zac1 controls cell cycle arrest function in neuronal progenitors through induction of p57 Kip2 via Tcf4 and provide evidence for cooperation between imprinted genes and a bHLH factor in early neurodevelopment.