title: A complex syndrome of left-right axis, central nervous system and axial skeleton defects in Zic3 mutant mice.
abstract: X-linked heterotaxy (HTX1) is a rare developmental disorder characterized by disturbances in embryonic laterality and other midline developmental field defects. HTX1 results from mutations in ZIC3, a member of the GLI transcription factor superfamily. A targeted deletion of the murine Zic3 locus has been created to investigate its function and interactions with other molecular components of the left-right axis pathway. Embryonic lethality is seen in approximately 50% of null mice with an additional 30% lethality in the perinatal period. Null embryos have defects in turning, cardiac development and neural tube closure. Malformations in live born null mice include complex congenital heart defects, pulmonary reversal or isomerism, CNS defects and vertebral/rib anomalies. Investigation of nodal expression in Zic3-deficient mice indicates that, although nodal is initially expressed symmetrically in the node, there is failure to maintain expression and to shift to asymmetric expression. Subsequent nodal and Pitx2 expression in the lateral plate mesoderm in these mice is randomized, indicating that Zic3 acts upstream of these genes in the determination of left-right asymmetry. The phenotype of these mice correctly models the defects found in human HTX1 and indicates an important role for Zic3 in both left-right and axial patterning.
authors.affiliation: Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Smita M
authors.initials: SM
authors.lastname: Purandare
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Ware
authors.forename: Kin Ming
authors.initials: KM
authors.lastname: Kwan
authors.forename: Marinella
authors.initials: M
authors.lastname: Gebbia
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Bassi
authors.forename: Jian Min
authors.initials: JM
authors.lastname: Deng
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.forename: Richard R
authors.initials: RR
authors.lastname: Behringer
authors.forename: John W
authors.initials: JW
authors.lastname: Belmont
authors.forename: Brett
authors.initials: B
authors.lastname: Casey
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D019521:Body Patterning / Q000235:genetics* / Q000502:physiology*; D001842:Bone and Bones / Q000002:abnormalities*; D002490:Central Nervous System / Q000002:abnormalities*; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal; D008040:Genetic Linkage; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055457:Nodal Protein; D009687:Nuclear Proteins; D010641:Phenotype; D013577:Syndrome; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics; D014960:X Chromosome / Q000235:genetics; D000097577:Homeobox Protein PITX2
chemical_list: D018398:Homeodomain Proteins; D055457:Nodal Protein; D009687:Nuclear Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000097577:Homeobox Protein PITX2; C526007:NODAL protein, human; C526008:Nodal protein, mouse; C491594:Zic3 protein, mouse