| First Author | Ke CY | Year | 2019 |
| Journal | Sci Signal | Volume | 12 |
| Issue | 593 | PubMed ID | 31387937 |
| Mgi Jnum | J:282087 | Mgi Id | MGI:6369862 |
| Doi | 10.1126/scisignal.aav7666 | Citation | Ke CY, et al. (2019) IRF6 and TAK1 coordinately promote the activation of HIPK2 to stimulate apoptosis during palate fusion. Sci Signal 12(593) |
| abstractText | Cleft palate is a common craniofacial defect caused by a failure in palate fusion. The palatal shelves migrate toward one another and meet at the embryonic midline, creating a seam. Transforming growth factor-beta3 (TGF-beta3)-induced apoptosis of the medial edge epithelium (MEE), the cells located along the seam, is required for completion of palate fusion. The transcription factor interferon regulatory factor 6 (IRF6) promotes TGF-beta3-induced MEE cell apoptosis by stimulating the degradation of the transcription factor DeltaNp63 and promoting the expression of the gene encoding the cyclin-dependent kinase inhibitor p21. Because homeodomain-interacting protein kinase 2 (HIPK2) functions downstream of IRF6 in human cancer cells and is required for DeltaNp63 protein degradation in keratinocytes, we investigated whether HIPK2 played a role in IRF6-induced DeltaNp63 degradation in palate fusion. HIPK2 was present in the MEE cells of mouse palatal shelves during seam formation in vivo, and ectopic expression of IRF6 in palatal shelves cultured ex vivo stimulated the expression of Hipk2 and the accumulation of phosphorylated HIPK2. Knockdown and ectopic expression experiments in organ culture demonstrated that p21 was required for HIPK2- and IRF6-dependent activation of caspase 3, MEE apoptosis, and palate fusion. Contact between palatal shelves enhanced the phosphorylation of TGF-beta-activated kinase 1 (TAK1), which promoted the phosphorylation of HIPK2 and palate fusion. Our findings demonstrate that HIPK2 promotes seam cell apoptosis and palate fusion downstream of IRF6 and that IRF6 and TAK1 appear to coordinately enhance the abundance and activation of HIPK2 during palate fusion. |
