Deregulation of ZIC Family Members in Oncogenesis.

In the last decade, the amount of investigations on the involvement of ZIC genes in the cancer field have exponentially expanded. In most cancer types, promoter methylation leads to silenced ZIC family members, but specific subsets of patients clearly show increased expression of one or head-to-head located ZIC genes in the respective tumor tissue. It is unclear at this stage how these transcription factors contribute to tumorigenesis, but the potential implications in pathways that are most frequently mutated in cancer such as the canonical Wnt, TGF-beta, and STAT-3 pathway are evident.

Zic2 mutation causes holoprosencephaly via disruption of NODAL signalling.

The ZIC2 transcription factor is one of the genes most commonly mutated in Holoprosencephaly (HPE) probands. Studies in cultured cell lines and mice have shown a loss of ZIC2 function is the pathogenic mechanism but the molecular details of this ZIC2 requirement remain elusive. HPE arises when signals that direct morphological and fate changes in the developing brain and facial primordia are not sent or received.

The ZIC gene family encodes multi-functional proteins essential for patterning and morphogenesis.

The zinc finger of the cerebellum gene (ZIC) discovered in Drosophila melanogaster (odd-paired) has five homologs in Xenopus, chicken, mice, and humans, and seven in zebrafish. This pattern of gene copy expansion is accompanied by a divergence in gene and protein structure, suggesting that Zic family members share some, but not all, functions. ZIC genes are implicated in neuroectodermal development and neural crest cell induction.

Transcription factor Zic2 inhibits Wnt/β-catenin protein signaling.

The Zic transcription factors play critical roles during embryonic development. Mutations in the ZIC2 gene are associated with human holoprosencephaly, but the etiology is still unclear. Here, we report a novel function for ZIC2 as a regulator of β-catenin·TCF4-mediated transcription.