Cleft lip, with or without cleft palate, occurs in around 1 in 700 human newborns, but little is known about the mechanisms involved. Now, on , Chengji Zhou and colleagues identify the Wnt co-receptor Lrp6 as being crucial for normal lip morphogenesis in mice. All mice in which Lrp6 is deleted develop a cleft lip with cleft palate. These defects correlate with blocked Wnt/β-catenin signalling and with reduced cell proliferation in the primordia of the lip and palate (known as the orofacial primordia) earlier in development. Concomitantly with reduced Wnt/β-catenin signalling, the expression of the homeobox genes Msx1 and Msx2, which are important for mesenchyme proliferation, is decreased in the orofacial primordia. Conversely,the expression of Raldh3, which encodes a retinoic acid-synthesising enzyme that counteracts tissue fusion, expands. The authors demonstrate that Msx1 and Msx2 are direct targets of Wnt/β-catenin signalling and conclude that Lrp6-mediated Wnt/β-catenin signalling regulates lip formation and fusion by balancing the activities of Msx1 and Msx2 with the opposing activity of Raldh3.
