title: Zac1 regulates cell cycle arrest in neuronal progenitors via Tcf4.
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 G1 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.
authors.affiliation: Max Planck Institute of Psychiatry, Molecular Neuroendocrinology, Munich, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Schmidt-Edelkraut
authors.forename: Guillaume
authors.initials: G
authors.lastname: Daniel
authors.forename: Anke
authors.initials: A
authors.lastname: Hoffmann
authors.forename: Dietmar
authors.initials: D
authors.lastname: Spengler
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000254:growth & development; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000378:metabolism*; D016193:G1 Phase / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D016147:Genes, Tumor Suppressor; D051379:Mice; D055495:Neurogenesis / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C493965:Cdkn1c protein, mouse; D018797:Cell Cycle Proteins; D050761:Cyclin-Dependent Kinase Inhibitor p57; C498423:Plagl1 protein, mouse; C090743:Tcf4 protein, mouse; D000073940:Transcription Factor 4; D014157:Transcription Factors