Bellchambers, Helen M.Ware, Stephanie M.2023-07-182023-07-182021Bellchambers HM, Ware SM. Loss of Zic3 impairs planar cell polarity leading to abnormal left-right signaling, heart defects and neural tube defects. Hum Mol Genet. 2021;30(24):2402-2415. doi:10.1093/hmg/ddab195https://hdl.handle.net/1805/34472Loss of function of ZIC3 causes heterotaxy (OMIM #306955), a disorder characterized by organ laterality defects including complex heart defects. 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. Here, we demonstrate Zic3 null mice undergo cilia positioning defects at the embryonic node consistent with impaired planar cell polarity (PCP). 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. 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. 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. 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.en-USPublisher PolicyCell polarityHeterotaxy syndromeHomeodomain proteinsMicrofilament proteinsNeural tube defectsTranscription factorsArticle