Research ArticleDevelopmental Biology

IRF6 and TAK1 coordinately promote the activation of HIPK2 to stimulate apoptosis during palate fusion

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Science Signaling  06 Aug 2019:
Vol. 12, Issue 593, eaav7666
DOI: 10.1126/scisignal.aav7666

HIPK2 promotes palate fusion

The palate arises from bilaterally symmetric primordia that migrate toward one another and fuse during embryonic development. Fusion is not complete until the seam cells along the border where the two palatal shelves meet are eliminated, a process that depends on transforming growth factor–β3 (TGF-β3) and the transcription factor IRF6. Ke et al. found that IRF6 directly promoted expression of the gene encoding the kinase HIPK2 and that this was required for seam cell apoptosis during palate fusion in mice. Contact between palatal shelves induced the phosphorylation of the TGF-β–activated kinase TAK1, which in turn promoted the phosphorylation of HIPK2. Thus, IRF6 and TAK1 cooperatively promote the activity of HIPK2 to drive the final stage of palate fusion.


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–β3 (TGF-β3)–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-β3–induced MEE cell apoptosis by stimulating the degradation of the transcription factor ΔNp63 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 ΔNp63 protein degradation in keratinocytes, we investigated whether HIPK2 played a role in IRF6-induced ΔNp63 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-β–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.

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