Lip abnormalities in Irf6 deficient mice

Background:

Van der Woude syndrome (VWS; OMIM#119300) is a highly penetrant, autosomal dominant orofacial clefting disorder. Clinically, the presence of lip pits accompanying a cleft of the lip, palate, uvula or combinations thereof are nearly pathognomonic for VWS. Mutations in IRF6 cause VWS, but the precise mechanism by which IRF6 influences lip and palate development is not known. Recently, we demonstrated that Irf6 deficient mice exhibit skin, limb, and craniofacial abnormalities. Subsequently, morphological studies identified abnormalities in both the lower and upper lip.

Objectives:

To further characterize these abnormalities we performed histological analysis.

Methods:

Cross sections of murine heads were stained with H&E at embryonic days (E) 14.5-17.5.

Results:

We observed bilateral involutions of the epithelium in the transition zone where the basal layer of the epithelium changes from epidermal to oral on both the mandible and maxilla. Also notable was anterior tongue adhesion to the hard palate and anterior floor of the oral cavity. The development of the lip abnormalities was marked by bilateral involutions invading at greater depth toward the lateral tissues, advancing into the epidermal and dermal tissues of the face and cheek. At a midsagittal section of these abnormalities the involutions anastomose, isolating the peripheral tissues. The involutions progress until complete isolation of the adjoining tissues results.

Conclusions:

Ongoing experiments will test two hypotheses regarding these involutions: that the cells isolated by an epithelial down growth undergo either apoptosis or that their isolation results in displacement of the entire tissue at once to form a lip pit. Further gene expression studies and murine models will continue to provide additional insights into the role of IRF6 in the developmental pathway in both facial and epithelial development.