Heterotaxy-spectrum heart defects in Zic3 hypomorphic mice

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.