title: Maternal and zygotic Zfp57 modulate NOTCH signaling in cardiac development.
abstract: Zfp57 is a maternal-zygotic effect gene that maintains genomic imprinting. Here we report that Zfp57 mutants exhibited a variety of cardiac defects including atrial septal defect (ASD), ventricular septal defect (VSD), thin myocardium, and reduced trabeculation. Zfp57 maternal-zygotic mutant embryos displayed more severe phenotypes with higher penetrance than the zygotic ones. Cardiac progenitor cells exhibited proliferation and differentiation defects in Zfp57 mutants. ZFP57 is a master regulator of genomic imprinting, so the DNA methylation imprint was lost in embryonic heart without ZFP57. Interestingly, the presence of imprinted DLK1, a target of ZFP57, correlated with NOTCH1 activation in cardiac cells. These results suggest that ZFP57 may modulate NOTCH signaling during cardiac development. Indeed, loss of ZFP57 caused loss of NOTCH1 activation in embryonic heart with more severe loss observed in the maternal-zygotic mutant. Maternal and zygotic functions of Zfp57 appear to play redundant roles in NOTCH1 activation and cardiomyocyte differentiation. This serves as an example of a maternal effect that can influence mammalian organ development. It also links genomic imprinting to NOTCH signaling and particular developmental functions.
authors.affiliation: Department of Developmental and Regenerative Biology, Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Yulia
authors.initials: Y
authors.lastname: Shamis
authors.affiliation: Department of Developmental and Regenerative Biology.
authors.forename: Dana E
authors.initials: DE
authors.lastname: Cullen
authors.affiliation: Department of Developmental and Regenerative Biology.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Proteomics, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing 100071, China; and.
authors.forename: Guan
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Developmental and Regenerative Biology.
authors.forename: Sheau-Fang
authors.initials: SF
authors.lastname: Ng
authors.affiliation: Department of Developmental and Regenerative Biology.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Department of Developmental and Regenerative Biology.
authors.forename: Fong T
authors.initials: FT
authors.lastname: Bell
authors.affiliation: Department of Developmental and Regenerative Biology.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Ray
authors.affiliation: Department of Developmental and Regenerative Biology.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Takikawa
authors.affiliation: Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, IL 60637.
authors.forename: Ivan P
authors.initials: IP
authors.lastname: Moskowitz
authors.affiliation: Department of Developmental and Regenerative Biology.
authors.forename: Chen-Leng
authors.initials: CL
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Proteomics, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing 100071, China; and.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Developmental and Regenerative Biology, Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Black Family Stem Cell Institute, and Xiajun.Li@mssm.edu.
authors.forename: Xiajun
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D049109:Cell Proliferation; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018392:Genomic Imprinting; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000196:embryology / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D032383:Myocytes, Cardiac / Q000473:pathology; D051880:Receptors, Notch / Q000378:metabolism*; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D014157:Transcription Factors / Q000378:metabolism; D015053:Zygote / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; C484469:Nkx2-5 protein, mouse; D051880:Receptors, Notch; D012097:Repressor Proteins; D014157:Transcription Factors; C501529:Zfp-57 protein, mouse
keywords: NOTCH; ZFP57; cardiac development; genomic imprinting; maternal-zygotic mutant
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