Zic3, a C2H2 zinc finger transcription factor, is crucial for early vertebrate embryo patterning. It has putative roles in multiple developmental signalling pathways involved in establishing the left-right axis. Zic3 is also important for midline neural patterning, and its function is linked to maintaining pluripotency of embryonic stem cells [1,2,3,7].

In Zic3 null mice, which recapitulate the human heterotaxy phenotype, there are cilia positioning defects at the embryonic node due to impaired planar cell polarity (PCP), leading to abnormal left-right signalling, heart defects, and neural tube defects. Zic3 interacts with PCP membrane protein Vangl2 and effector genes Rac1 and Daam1, and its absence disrupts the expression of PCP components and reduces phosphorylation of DVL2 during left-right axis determination. Conditional deletion in mice shows Zic3 is required in the primitive streak and migrating mesoderm for proper left-right patterning and cardiac development [4,5]. In Xenopus embryos, overexpression of Zic3 on the right side altered heart and gut looping, and its expression in the mesoderm is induced by activin or Vg1, suggesting it participates in left-sided signalling upstream of Xnr1 and Pitx2 [6].

In conclusion, Zic3 is essential for left-right axis formation, midline neural patterning, and maintaining pluripotency. Studies using Zic3 knockout and conditional knockout mouse models, as well as Xenopus models, have revealed its role in these processes and in diseases such as heterotaxy, congenital heart disease, and neural tube defects. These models have provided key insights into the molecular mechanisms underlying Zic3-related biological functions and disease conditions [1,4,5,6].