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Our laboratory is interested in understanding the role of ZIC3 in body pattern formation and the development of left-right asymmetry. X-linked heterotaxy (HTX-1, MIM 306955) results from mutations in ZIC3, a member of the GLI transcription factor superfamily. Individuals with HTX1 have a number of congenital malformations including complex congenital heart disease, gut malrotation, abnormalities of spleen position and number, and renal and anal malformations.
We developed a mouse model of X-linked heterotaxy by targeted deletion of the murine ZIC3 locus and are using this and other mouse models to investigate the functions of ZIC3. We are specifically focusing on its interactions with other molecular components of the left-right patterning pathway immediately prior to and during cardiac looping. A second focus, utilizing both mouse models and Xenopus, investigates the role of ZIC3 during gastrulation.
Previously, we performed ZIC3 mutation screening on individuals with familial and sporadic heterotaxy to more clearly define the clinical spectrum of this disorder. This molecular data is being utilized to engineer similar mutations in the mouse to create mouse models of human malformation. Both in vitro and in vivo studies are ongoing to delineate genotype-phenotype correlations and further explore the functional domains of the ZIC3 gene.
The importance of ZIC3 developmentally is clearly shown by the vast array of phenotypic abnormalities seen in both mouse and human; however, the precise developmental function of ZIC3 is currently unknown. We are studying how ZIC3 loss of function influences limb phenotype, Shh pathway gene expression level and Gli3 protein processing to gain more insight into the role and function of ZIC3 itself. The role of ZIC3 in other important developmental pathways is also being investigated to further understand the temporal and spatial requirement for ZIC3 in embryonic development.
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