Grainy head-like 3 (Grhl3) is a member of a large gene family, which encodes highly conserved transcription factors that regulate the formation and maintenance of the integument in diverse species. Constitutive deletion of Grhl3 during development induces neural tube defects, and the mice die as newborns due to failure of the skin barrier to form. Conditional deletion of Grhl3 after birth does not result in epidermal barrier regression, but adult mice lacking this factor develop squamous cell carcinoma (SCC) driven by unrestrained PI3K/AKT signaling. Recently, we have also shown that these mice are susceptible to head and neck SCC (HNSCC). Surprisingly, these tumors do not exhibit PI3K/AKT activation, but instead manifest high levels of the proto-oncogene c-Myc. GRHL3 target gene selectivity in different tissues explains this apparent dichotomy.
To assess how the skin barrier is maintained in adult Grhl3-null mice we explored redundancy between family members in this context. Grhl1 knockout mice display abnormal anchorage of hair follicles but exhibit no skin barrier defect. However, when these mice are crossed with conditional knockout mice that delete Grhl3 from P1, the normal barrier that forms in utero regresses completely, and the pups die at day 2-3 from dehydration. We are currently exploring the molecular mechanisms that underpin loss of barrier function in these mice.