Recent insights into the role of IRF6 in craniofacial and skin development

Abstract

Genetic variation in Interferon Regulatory Factor 6 (IRF6) causes, and contributes risk for, orofacial clefting disorders. In one of these disorders, in addition to orofacial clefts, individuals have skin webbing of the lower limbs. Thus, IRF6 is a key component of palatal and skin development in humans. In mice, Irf6 is expressed in the medial edge epithelium (MEE) that is dependent on Tgfb signaling. And, Irf6 is expressed in the spinous layer of the epidermis. Moreover, mice deficient for Irf6 have abnormal skin, limb and craniofacial development, including cleft palate. In the epidermis, in vivo and in vitro analyses demonstrate that Irf6 is necessary for keratinocyte differentiation. Furthermore, keratinocytes from Irf6–/– epidermis fail to close a scratch wound and display abnormal clonal growth, suggesting abnormal cellular proliferation and migration. In the palate, growth of the shelves is not defective, but they fail to elevate above the tongue, may be due to oral adhesions. The palatal epithelium is highly adherent, but the MEE fails to undergo its normal pattern of dissolution. Mice that are compound heterozygotes for the null and hypomorphic alleles (Irf6–/neo) display less severe abnormalities than the Irf6 deficient mice. In the oral cavity, Irf6–/neo mice have less severe oral adhesions. We are assessing the Irf6–/neo mice for defects in palatal development and epithelial differentiation.