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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Research Article Cell biology

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 7

p63/IRF6 signaling pathway and Tfap2a expression in the FNP are affected by altering SHH signaling.

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p63/IRF6 signaling pathway and Tfap2a expression in the FNP are affected...
(A–D) Tp63 expression in E11.0 embryos. (A) Tp63 is strongly expressed at the lambdoidal region in control embryos (red arrowhead; orientation is the same as that shown in Figure 2, I–L). (B) Hhatcreface Ptch1wiggable embryos showed reduced Tp63 expression at the lambdoidal region (red arrowhead), and (C) Ptch1wiggable embryos showed an even lower expression level. (D) Conversely, Hhatcreface embryos showed expanded Tp63 expression in LNP (red arrowhead). (E–H) Irf6 expression in E11.0 embryos. (E) Irf6 expression at the lambdoidal region in control embryos is similar to Tp63 expression (red arrowhead). Irf6 expression was downregulated in both (F) Hhatcreface Ptch1wiggable (red arrowhead) and (G) Ptch1wiggable embryos. (H) Similar to Tp63, Irf6 showed expanded expression in Hhatcreface embryos (red arrowhead; orientation is the same as that shown in Figure 2, I–L). (I–L) Tfap2a expression in E11.0 embryos. (I) Tfap2a was expressed at mesenchymal cells in MNP (red arrow in I–L) and LNP (red arrowheads in I–L) in control embryos. The expression was attenuated in (K) Ptch1wiggable and (J) Hhatcreface Ptch1wiggable embryos, (L) while Hhatcreface embryos maintained expression (orientation is the same as that shown in Figure 2, E–H). Scale bars: 200 μm.