title: Craniofacial, skeletal, and cardiac defects associated with altered embryonic murine Zic3 expression following targeted insertion of a PGK-NEO cassette.
abstract: Mutation in ZIC3 (OMIM #306955), a zinc finger transcription factor, causes heterotaxy (situs ambiguus) or isolated congenital heart defects in humans. Mice bearing a null mutation in Zic3 have left-right patterning defects with associated cardiovascular, vertebra/rib, and central nervous system malformations. Although XZic3 is thought to play a critical role in Xenopus neural crest development, no defects in tissues derived from neural crest are apparent in adult Zic3(null) mice. In this study we have characterized the effect of a PGK-neo cassette insertion 5' of the Zic3 locus. The Zic3 transcript in this new allele is up-regulated in ES cells and in E9.0 embryos, but no ectopic expression was detected. Unlike the Zic3(null) mutation in which only 20% of mutant animals survive to adulthood, there was no evidence of excess fetal death caused by the Zic3(neo) allele. Zic3(neo) mutant mice exhibited hemifacial microsomia, asymmetric low set ears, axial skeletal defects, kyphosis and scoliosis; a combination of defects which mimics Goldenhar Syndrome. Some Zic3(neo) mice had evidence of left-right axis patterning defects, but cardiac malformation was much less common than in the Zic3(null) mutants. A six-week old hemizygous mouse was found to have thoraco-cervical ectopia cordis, an extremely rare congenital malformation in humans and for which there is no precedent in a mouse model.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Lirong
authors.initials: L
authors.lastname: Zhu
authors.forename: Jian Lan
authors.initials: JL
authors.lastname: Peng
authors.forename: Karine G
authors.initials: KG
authors.lastname: Harutyunyan
authors.forename: Monica D
authors.initials: MD
authors.lastname: Garcia
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Justice
authors.forename: John W
authors.initials: JW
authors.lastname: Belmont
mesh_terms: D000483:Alleles; D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities*; D019465:Craniofacial Abnormalities / Q000235:genetics*; D003413:Cricoid Cartilage / Q000002:abnormalities; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism; D018390:Gene Targeting; D006330:Heart Defects, Congenital / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006928:Hyoid Bone / Q000002:abnormalities; D019868:Kanamycin Kinase / Q000235:genetics; D051379:Mice; D010735:Phosphoglycerate Kinase / Q000235:genetics; D013121:Spinal Curvatures / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; C491594:Zic3 protein, mouse; D019868:Kanamycin Kinase; D010735:Phosphoglycerate Kinase