Heterotaxy-spectrum heart defects in Zic3 hypomorphic mice

BACKGROUND: Mutations in 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 to Zic3 null mice. Concordance of early left-right molecular marker abnormalities and later anatomic abnormalities suggests the primary effect of Zic3 in heart development occurs during left-right patterning. Cardiac specific gene expression of Nppa (ANF) and Tbx5 marked the proper morphological locations in the heart regardless of looping abnormalities. CONCLUSIONS: Zic3 hypomorphic mice are a useful model 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 the primary effect of Zic3 on cardiac development occurs during left-right patterning.