title: Casz1 is required for cardiomyocyte G1-to-S phase progression during mammalian cardiac development.
abstract: Organ growth occurs through the integration of external growth signals during the G1 phase of the cell cycle to initiate DNA replication. Although numerous growth factor signals have been shown to be required for the proliferation of cardiomyocytes, genetic studies have only identified a very limited number of transcription factors that act to regulate the entry of cardiomyocytes into S phase. Here, we report that the cardiac para-zinc-finger protein CASZ1 is expressed in murine cardiomyocytes. Genetic fate mapping with an inducible Casz1 allele demonstrates that CASZ1-expressing cells give rise to cardiomyocytes in the first and second heart fields. We show through the generation of a cardiac conditional null mutation that Casz1 is essential for the proliferation of cardiomyocytes in both heart fields and that loss of Casz1 leads to a decrease in cardiomyocyte cell number. We further report that the loss of Casz1 leads to a prolonged or arrested S phase, a decrease in DNA synthesis, an increase in phospho-RB and a concomitant decrease in the cardiac mitotic index. Taken together, these studies establish a role for CASZ1 in mammalian cardiomyocyte cell cycle progression in both the first and second heart fields.
authors.affiliation: University of North Carolina McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599-3280, USA Department of Genetics, UNC-Chapel Hill, Chapel Hill, NC 27599-3280, USA.
authors.forename: Kerry M
authors.initials: KM
authors.lastname: Dorr
authors.affiliation: University of North Carolina McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599-3280, USA Department of Genetics, UNC-Chapel Hill, Chapel Hill, NC 27599-3280, USA.
authors.forename: Nirav M
authors.initials: NM
authors.lastname: Amin
authors.affiliation: University of North Carolina McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599-3280, USA Department of Genetics, UNC-Chapel Hill, Chapel Hill, NC 27599-3280, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Kuchenbrod
authors.affiliation: Department of Biology, UNC-Chapel Hill, Chapel Hill, NC 27599-3280, USA.
authors.forename: Hanna
authors.initials: H
authors.lastname: Labiner
authors.affiliation: University of North Carolina McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599-3280, USA Department of Genetics, UNC-Chapel Hill, Chapel Hill, NC 27599-3280, USA.
authors.forename: Marta S
authors.initials: MS
authors.lastname: Charpentier
authors.affiliation: Department of Genetics, UNC-Chapel Hill, Chapel Hill, NC 27599-3280, USA Neuroscience Center, UNC-Chapel Hill, Chapel Hill, NC 27599-3280, USA.
authors.forename: Larysa H
authors.initials: LH
authors.lastname: Pevny
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Andy
authors.initials: A
authors.lastname: Wessels
authors.affiliation: University of North Carolina McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599-3280, USA Department of Genetics, UNC-Chapel Hill, Chapel Hill, NC 27599-3280, USA Department of Biology, UNC-Chapel Hill, Chapel Hill, NC 27599-3280, USA frank_conlon@med.unc.edu.
authors.forename: Frank L
authors.initials: FL
authors.lastname: Conlon
mesh_terms: D000818:Animals; D019070:Cell Lineage; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D016193:G1 Phase; D006321:Heart / Q000196:embryology*; D019426:Integrases / Q000378:metabolism; D008297:Male; D008322:Mammals / Q000196:embryology*; D051379:Mice; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D016196:S Phase; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C000600132:CASZ1 protein, mouse; D004268:DNA-Binding Proteins; D014157:Transcription Factors; C045073:Cre recombinase; D019426:Integrases
keywords: CASZ1; Cardiomyocyte; Congenital heart disease; First heart field; Heart development; Mouse; Proliferation; Second heart field