Heterotaxy-spectrum heart defects in Zic3 hypomorphic mice

Allison M. Haaning, Malgorzata E. Quinn, Stephanie M. Ware

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Background:Mutations in Zinc Finger Protein of the Cerebellum 3 (ZIC3) cause X-linked heterotaxy and isolated cardiovascular malformations. Recent data suggest a potential cell-autonomous role for Zic3 in myocardium via regulation of Nppa and Tbx5. We sought to develop a hypomorphic Zic3 mouse to model human heterotaxy and investigate developmental mechanisms underlying variability in cardiac phenotypes.Methods:Zic3 hypomorphic mice were created by targeted insertion of a neomycin cassette and investigated by gross, histologic, and molecular methods.Results:Low-level Zic3 expression is sufficient for partial rescue of viability as compared with Zic3 null mice. Concordance of early left-right molecular marker abnormalities and later anatomic abnormalities suggests that the primary effect of Zic3 in heart development occurs during left-right patterning. Cardiac-specific gene expression of Nppa (atrial natriuretic factor) and Tbx5 marked the proper morphological locations in the heart regardless of looping abnormalities.Conclusion:Zic3 hypomorphic mice are useful models to investigate the variable cardiac defects resulting from a single genetic defect. Low-level Zic3 expression rescues the left pulmonary isomerism identified in Zic3 null embryos. Our data do not support a direct role for Zic3 in the myocardium via regulation of Nppa and Tbx5 and suggest that the primary effect of Zic3 on cardiac development occurs during left-right patterning.

Original languageEnglish (US)
Pages (from-to)494-502
Number of pages9
JournalPediatric Research
Volume74
Issue number5
DOIs
StatePublished - Nov 1 2013
Externally publishedYes

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

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