<i>MCS9.7</i> Enhancer activity is highly, but not completely, associated with expression of Irf6 and p63

Fakhouri, Walid D.; Rhea, Lindsey; Du, Tianli; Sweezer, Eileen; Morrison, Harris; FitzPatrick, David R.; Yang, Baoli; Dunnwald, Martine; Schutte, Brian C.

doi:10.1002/dvdy.23751

Cited by 26 publications

(60 citation statements)

References 20 publications

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“…But the timing and location of TGFβ3 during palatogenesis suggests that TGFβ3 may contribute in MEE differentiation and periderm degeneration. Evidence also supports the role of IRF6 and ΔNp63 in MEE differentiation and maintenance through several pathways, including Wnt, Ephrin, TGFβ1, and Notch/Jag2 (Richardson et al, ; Lee et al, ; Murillo et al, ; Richardson et al, ; Risley et al, ; Moretti et al, ; Thomason et al, ; Yu et al, ; Ferretti et al, ; Iordanskaia and Nawshad, ; Fakhouri et al, ; Barrio et al, ; Kurosaka et al, ). During palatogenesis, the MEE cell surface is covered with a periderm layer, which prevents MEE cells from premature adhesion to other tissues within the oral cavity (Fitchett and Hay, ).…”

Section: Discussionmentioning

confidence: 85%

TGFβ3 Regulates Periderm Removal Through ΔNp63 in the Developing Palate

Liu

et al. 2015

Journal Cellular Physiology

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The periderm is a flat layer of epithelium created during embryonic development. During palatogenesis, the periderm forms a protective layer against premature adhesion of the oral epithelia, including the palate. However, the periderm must be removed in order for the medial edge epithelia (MEE) to properly adhere and form a palatal seam. Improper periderm removal results in a cleft palate. Although the timing of transforming growth factor β3 (TGFβ3) expression in the MEE coincides with periderm degeneration, its role in periderm desquamation is not known. Interestingly, murine models of knockout (-/-) TGFβ3, interferon regulatory factor 6 (IRF6) (-/-), and truncated p63 (ΔNp63) (-/-) are born with palatal clefts because of failure of the palatal shelves to adhere, suggesting that these genes regulate palatal epithelial differentiation. However, despite having similar phenotypes in null mouse models, no studies have analyzed the possible association between the TGFβ3 signaling cascade and the IRF6/ΔNp63 genes during palate development. Recent studies indicate that regulation of ΔNp63, which depends on IRF6, facilitates epithelial differentiation. We performed biochemical analysis, gene activity and protein expression assays with palatal sections of TGFβ3 (-/-), ΔNp63 (-/-), and wild-type (WT) embryos, and primary MEE cells from WT palates to analyze the association between TGFβ3 and IRF6/ΔNp63. Our results suggest that periderm degeneration depends on functional TGFβ3 signaling to repress ΔNp63, thereby coordinating periderm desquamation. Cleft palate occurs in TGFβ3 (-/-) because of inadequate periderm removal that impedes palatal seam formation, while cleft palate occurs in ΔNp63 (-/-) palates because of premature fusion.

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Section: Discussionmentioning

confidence: 85%

TGFβ3 Regulates Periderm Removal Through ΔNp63 in the Developing Palate

Liu

et al. 2015

Journal Cellular Physiology

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“…We tested both rs2235371, located in IRF6 , and rs642961, located in an upstream enhancer (Fakhouri et al, 2012; Rahimov et al, 2008), because although rs642961 is etiologic and confers risk for CL, it does not completely account for the association with rs2235371 (Rahimov et al, 2008). We found a marginal interaction between these SNPs, (p=0.04 and p=0.07, respectively).…”

Section: Resultsmentioning

confidence: 99%

“…Increasing evidence suggests etiologic variants, particularly for complex diseases, will occur in noncoding regions of the genome (Ernst et al, 2011; Visel et al, 2009). To date, only one common, etiologic variant (rs642961) has been identified in a recognized cleft candidate gene, IRF6 , and it resides in an enhancer element near this gene (Fakhouri et al, 2012; Rahimov et al, 2008). We hypothesize common etiologic variants for the 1p22 locus may reside in regulatory elements of ARHGAP29 .…”

Section: Discussionmentioning

confidence: 99%

Expression and mutation analyses implicate ARHGAP29 as the etiologic gene for the cleft lip with or without cleft palate locus identified by genome‐wide association on chromosome 1p22

Leslie

Mansilla

Biggs

et al. 2012

Birth Defects Research

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113

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Background Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect with complex etiology reflecting the action of multiple genetic and/or environmental factors. Genome wide association studies have successfully identified five novel loci associated with NSCL/P including a locus on 1p22.1 near the ABCA4 gene. Since neither expression analysis nor mutation screening support a role for ABCA4 in NSCL/P, we investigated the adjacent gene ARHGAP29. Methods Mutation screening for ARHGAP29 protein coding exons was conducted in 180 individuals with NSCL/P and controls from the US and the Philippines. Nine exons with variants in ARHGAP29 were then screened in an independent set of 872 cases and 802 controls. Arhgap29 expression was evaluated using in situ hybridization in murine embryos. Results Sequencing of ARHGAP29 revealed eight potentially deleterious variants in cases including a frameshift and a nonsense variant. Arhgap29 showed craniofacial expression and was reduced in a mouse deficient for Irf6, a gene previously shown to have a critical role in craniofacial development. Conclusion The combination of genome wide association, rare coding sequence variants, craniofacial specific expression and interactions with IRF6 support a role for ARHGAP29 in NSCL/P and as the etiologic gene at the 1p22 GWAS locus for NSCL/P. This work suggests a novel pathway in which the IRF6 gene regulatory network interacts with the Rho pathway via ARHGAP29.

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“…Irf6 has also been identified as a candidate gene for isolated CL/P as well as Van der Woude's syndrome (54). Interestingly, recent studies demonstrated that p63 directly activates Irf6 transcription, allowing epithelial cells to exit the cell cycle during proper processes fusion (16,17,36,55). Furthermore, inhibiting the p63/IRF6 signaling cascade had been shown to facilitate the persistence of excessive periderm cells in the secondary palate, which is mechanistically associated with the pathogenesis of CL/P (17).…”

Section: Methodsmentioning

confidence: 99%

Disrupting hedgehog and WNT signaling interactions promotes cleft lip pathogenesis

Kurosaka¹,

Iulianella²,

Williams³

et al. 2014

J. Clin. Invest.

102

128

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Cleft lip, which results from impaired facial process growth and fusion, is one of the most common cranio facial birth defects. Many genes are known to be involved in the etiology of this disorder; however, our under standing 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 investi gation 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.

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MCS9.7 Enhancer activity is highly, but not completely, associated with expression of Irf6 and p63

Cited by 26 publications

References 20 publications

TGFβ3 Regulates Periderm Removal Through ΔNp63 in the Developing Palate

TGFβ3 Regulates Periderm Removal Through ΔNp63 in the Developing Palate

Expression and mutation analyses implicate ARHGAP29 as the etiologic gene for the cleft lip with or without cleft palate locus identified by genome‐wide association on chromosome 1p22

Disrupting hedgehog and WNT signaling interactions promotes cleft lip pathogenesis

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