Disrupting hedgehog and WNT signaling interactions promotes cleft lip pathogenesis
Hiroshi Kurosaka, … , Trevor Williams, Paul A. Trainor
Hiroshi Kurosaka, … , Trevor Williams, Paul A. Trainor
Published March 3, 2014
Citation Information: J Clin Invest. 2014;124(4):1660-1671. https://doi.org/10.1172/JCI72688.
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Disrupting hedgehog and WNT signaling interactions promotes cleft lip pathogenesis

Abstract

Cleft lip, which results from impaired facial process growth and fusion, is one of the most common craniofacial birth defects. Many genes are known to be involved in the etiology of this disorder; however, our understanding of cleft lip pathogenesis remains incomplete. In the present study, we uncovered a role for sonic hedgehog (SHH) signaling during lip fusion. Mice carrying compound mutations in hedgehog acyltransferase (Hhat) and patched1 (Ptch1) exhibited perturbations in the SHH gradient during frontonasal development, which led to hypoplastic nasal process outgrowth, epithelial seam persistence, and cleft lip. Further investigation revealed that enhanced SHH signaling restricts canonical WNT signaling in the lambdoidal region by promoting expression of genes encoding WNT inhibitors. Moreover, reduction of canonical WNT signaling perturbed p63/interferon regulatory factor 6 (p63/IRF6) signaling, resulting in increased proliferation and decreased cell death, which was followed by persistence of the epithelial seam and cleft lip. Consistent with our results, mutations in genes that disrupt SHH and WNT signaling have been identified in both mice and humans with cleft lip. Collectively, our data illustrate that altered SHH signaling contributes to the etiology and pathogenesis of cleft lip through antagonistic interactions with other gene regulatory networks, including the canonical WNT and p63/IRF6 signaling pathways.

Authors

Hiroshi Kurosaka, Angelo Iulianella, Trevor Williams, Paul A. Trainor

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Figure 2

Mutation in Hhat and Ptch1 genes modifies facial process growth and fusion, as shown by nuclear fluorescent imaging.

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Mutation in Hhat and Ptch1 genes modifies facial process growth and fusi...
(A–H) Lateral view of embryos, with genotypes shown at the top and embryonic stages shown at the left. (A–D) At E10.0, each embryo developed morphologically similar FNPs. (E) At E11.0, MNP and LNP begin to develop in control embryos. (F and G) Hhatcreface Ptch1wiggable and Ptch1wiggable embryos developed hypoplastic MNPs and LNPs. (H) Hhatcreface embryos showed shorter distance between left and right nasal pit. (I–L) Frontal view of embryos of each indicated genotype at E11.5. (I and J) Obvious fissure exists between MNP and LNP in Hhatcreface Ptch1wiggable embryos compared with that in control embryos (red arrowheads). (K) Ptch1wiggable embryos showed severely affected FNPs. (L) MNP was not detectable from an external view of Hhatcreface embryo head. (M–R) Ventral view of maxillary complex. (M and N) MNP and LNP failed to fuse in Hhatcreface Ptch1wiggable embryos and left larger gap between those processes compared with control embryos (red arrowheads). (Q and R) At E12.5, Hhatcreface Ptch1wiggable embryos showed obvious cleft lip and primary palate compared with control embryos. MXP, maxillary process; BA, branchial arch; MN, mandible. Scale bars: 200 μm.