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 language | English (US) |
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Pages (from-to) | 494-502 |
Number of pages | 9 |
Journal | Pediatric Research |
Volume | 74 |
Issue number | 5 |
DOIs | |
State | Published - Nov 2013 |
Externally published | Yes |