![]() In patients, 75% of familial X-linked heterotaxy can be explained by mutation of ZIC3 ( 6) and mouse, frog and zebrafish models of Zic3 deficiency recapitulate this phenotype ( 7, 8). One gene causing heterotaxy is ZIC3, a member of the Zinc finger of the cerebellum (ZIC) family of transcription factors. Because LR patterning has multiple roles in organ development, these heart defects can co-occur with other organ laterality defects, which together are classified as heterotaxy syndrome. ![]() These genes are required for establishment of left–right (LR) patterning which is essential for later heart looping, thus disruption of the establishment of LR patterning is associated with a range of heart defects. Heart defects can be caused by events prior to heart formation and thus involve genes not expressed in the heart ( 2), such as Noto, Lhx1 and Foxj1 ( 3–5). These results demonstrate that ZIC3 interacts with PCP signaling during early development, identifying a novel role for this transcription factor, and adding additional evidence about the importance of PCP function for normal LR patterning and subsequent heart development.Ĭongenital heart defects affect almost 1% of births and are collectively the most common birth defect ( 1). ![]() Gene and protein expression analyses indicate that Zic3 null embryos display disrupted expression of PCP components and reduced phosphorylation of the core PCP protein DVL2 at the time of LR axis determination. Furthermore, we show that Zic3 displays a genetic interaction with the PCP membrane protein Vangl2 and the PCP effector genes Rac1 and Daam1 resulting in increased frequency and severity of neural tube and heart defects. Cell-based assays demonstrate that ZIC3 must enter the nucleus to regulate PCP and identify multiple critical ZIC3 domains required for regulation of PCP signaling. Here, we demonstrate Zic3 null mice undergo cilia positioning defects at the embryonic node consistent with impaired planar cell polarity (PCP). Studies using Zic3 mutant mice have demonstrated that loss of Zic3 causes heterotaxy due to defects in establishment of left–right (LR) signaling, but the mechanistic basis for these defects remains unknown.
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