Cleft lip with or without cleft palate (CL/P) is the most frequent facial birth defect in humans, with an incidence of 1 in 700 live births. Current treatment requires multiple cycles of surgery, speech therapy and orthodontics, placing a great burden on those born with the defect.

CL/P is caused by the disruption of the genetic programs that guide facial development. In a new study, genetic methods were used for the first time to successfully repair cleft lip in mouse embryos. By mutating three Pbx genes in the embryonic cell layer that gives rise to the lip and nose, Licia Selleri and her team at Weill Medical College of Cornell University (New York, NY) created the first multi-gene transgenic mouse model for CL/P (Dev. Cell 21, 627–641; 2011).

Pbx genes are highly expressed in the area where the developing layers of facial tissue fuse together. Pbx proteins coordinate cellular activities crucial for facial development by regulating a chain of signaling molecules that have been implicated in CL/P, including Wnt, best known for their roles in development. This signaling pathway is conserved across mammalian species. Only the mouse lines lacking multiple Pbx genes simultaneously in the facial tissue layer exhibited complete CL/P. This is consistent with human CL/P, which is caused by multiple concomitant gene mutations.

The mouse embryos with multiple Pbx mutations had reduced or absent Wnt activity and disrupted Wnt signaling, suggesting that Pbx-directed Wnt signaling is required for proper facial development. In fact, in the embryos with compound Pbx mutations, restoring the Wnt signaling pathway was sufficient to correct the defects: the cleft lips in all of these animals completely disappeared. Selleri explained, “To my knowledge, this is the first time that anyone has corrected this defect in embryos, and we really show here that Wnt is a critical factor. This is a provocative result because it opens a completely new avenue of strategies for tissue repair.”

In follow-up studies, the researchers plan to supply Wnt molecules directly, or implant tissues that would deliver Wnt molecules, to Pbx-mutated mouse embryos placed within a uterus-like environment. This approach of delivering Wnt signals directly to the uterus would be more realistic for implementation in humans. If the Wnt treatment is sufficient to correct or even prevent the facial developmental abnormalities, it may provide a means of correcting CL/P before it even occurs.