title: Elevated levels of ZAC1 disrupt neurogenesis and promote rapid in vivo reprogramming.
abstract: The zinc finger transcription factor Zac1 is expressed in dividing progenitors of the nervous system with expression levels negatively controlled by genomic imprinting. To explore the consequences of elevated ZAC1 levels during neurogenesis we overexpressed it in the developing CNS. Increased levels of ZAC1 rapidly promoted upregulation of CDK inhibitors P57 and P27 followed by cell cycle exit. Surprisingly this was accompanied by stalled neuronal differentiation. Genome wide expression analysis of cortical cells overexpressing Zac1 revealed a decrease in neuronal gene expression and an increased expression of imprinted genes, factors regulating mesoderm formation as well as features of differentiated muscle. In addition, we observed a rapid induction of several genes regulating pluripotency. Taken together, our data suggests that expression levels of Zac1 need to be kept under strict control to avoid premature cell cycle exit, disrupted neurogenesis and aberrant expression of non-neuronal genes including pluripotency associated factors.
authors.affiliation: Department of Cell and Molecular Biology, Ludwig Institute for Cancer Research, Karolinska Institutet, Nobels väg 3, 171 77, Stockholm, Sweden.
authors.forename: Vilma
authors.initials: V
authors.lastname: Rraklli
authors.affiliation: Department of Cell and Molecular Biology, Ludwig Institute for Cancer Research, Karolinska Institutet, Nobels väg 3, 171 77, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Södersten
authors.affiliation: Department of Cell and Molecular Biology, Ludwig Institute for Cancer Research, Karolinska Institutet, Nobels väg 3, 171 77, Stockholm, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Nyman
authors.affiliation: Department of Cell and Molecular Biology, Ludwig Institute for Cancer Research, Karolinska Institutet, Nobels väg 3, 171 77, Stockholm, Sweden.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Hagey
authors.affiliation: Department of Cell and Molecular Biology, Ludwig Institute for Cancer Research, Karolinska Institutet, Nobels väg 3, 171 77, Stockholm, Sweden. Electronic address: johan.holmberg@licr.ki.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Holmberg
mesh_terms: D000818:Animals; D001483:Base Sequence; D019521:Body Patterning; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D065150:Cellular Reprogramming; D002645:Chickens; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D016147:Genes, Tumor Suppressor; D016678:Genome; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009132:Muscles / Q000166:cytology; D054259:Neural Tube / Q000196:embryology / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology; D039904:Pluripotent Stem Cells / Q000378:metabolism; D011485:Protein Binding; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C493965:Cdkn1c protein, mouse; D018797:Cell Cycle Proteins; D050761:Cyclin-Dependent Kinase Inhibitor p57; C498423:Plagl1 protein, mouse; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors
keywords: Differentiation; Imprinting; Neurogenesis; Pluripotency; Reprogramming; Transcription