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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 Article has an altmetric score of 10

Disrupting hedgehog and WNT signaling interactions promotes cleft lip pathogenesis

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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 5

Canonical WNT signaling is affected by altering SHH signaling during craniofacial development.

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Canonical WNT signaling is affected by altering SHH signaling during cra...
(A–D) Lateral views of heads of LacZ-stained E10.0 embryos of the indicated genotypes crossed with TOPgal mice (orientation is the same as that shown in Figure 2, A–D). (D) Hhatcreface embryos showed LacZ expression at LNP (red arrowhead), (A–C) while none of other embryos showed it. (E–H) Ventral views of E10.5 embryo MNPs (yellow dotted lines) and LNPs (red dotted lines) of each indicated genotype (orientation is the same as that shown in Figure 2, I–L). (F and G) Hhatcreface Ptch1wiggable and Ptch1wiggable embryos both showed noticeable reduction of LacZ expression in MNPs and LNPs compared with controls (E). (H) Hhatcreface embryos showed expanded LacZ expression in LNP. (I–L) Ventral views of E11.0 FNPs of each indicated genotype (orientation is the same as that shown in Figure 2, I–L). (I) Control embryos strongly expressed LacZ at the lambdoidal region where the MNP and LNP fuse (red arrowhead). (J) Hhatcreface Ptch1wiggable embryos showed reduced expression of LacZ at the lambdoidal region (red arrowhead). (K) Ptch1wiggable embryos showed even more reduction at FNPs. (M–P) Frontal sections of LacZ-stained embryos at E11.0. (M) Control embryos showed strong LacZ expression at epithelial seam and nasal epithelium (red arrowheads). (N) Hhatcreface Ptch1wiggable embryo LacZ expression was restricted compared with that of control embryos (red arrowheads). (O) Ptch1wiggable embryos showed very weak LacZ expression, and (P) Hhatcreface mice still maintained LacZ expression in FNPs. Scale bars: 200 μm (A–L); 50 μm (M–P).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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