Full Spectrum of Postnatal Tooth Phenotypes in a Novel <i>Irf6</i> Cleft Lip Model

Chu, Emily Y.; Tamasas, Basma; Fong, Helen; Foster, Brian L.; Lacourse, M. R.; Tran, A.B.; Martin, James F.; Schutte, Brian C.; Somerman, M. J.; Cox, Timothy C.

doi:10.1177/0022034516656787

Cited by 31 publications

(45 citation statements)

References 40 publications

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“…This interaction masks the receptor binding sites on GDF11 (Walker et al, 2017). Homozygous Fst knockout mice exhibit cleft palate, whereas Keratin14-driven epithelial-specific conditional knockout of the gene shows altered tooth cusp morphology and delayed third molar development in mice, similar to that reported for the major CL/P gene, Irf6 (Blackburn et al, 2012;Chu et al, 2016).…”

Section: Discussionsupporting

confidence: 62%

Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans

Cox

Lidral²,

McCoy

et al. 2019

Human Mutation

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Cleft lip with or without cleft palate (CL/P) is generally viewed as a complex trait with multiple genetic and environmental contributions. In 70% of cases, CL/P presents as an isolated feature and/or deemed nonsyndromic. In the remaining 30%, CL/P is associated with multisystem phenotypes or clinically recognizable syndromes, many with a monogenic basis. Here we report the identification, via exome sequencing, of likely pathogenic variants in two genes that encode interacting proteins previously only linked to orofacial clefting in mouse models. A variant in GDF11 (encoding growth differentiation factor 11), predicting a p.(Arg298Gln) substitution at the Furin protease cleavage site, was identified in one family that segregated with CL/P and both rib and vertebral hypersegmentation, mirroring that seen in Gdf11 knockout mice. In the second family in which CL/P was the only phenotype, a mutation in FST (encoding the GDF11 antagonist, Follistatin) was identified that is predicted to result in a p.(Cys56Tyr) substitution in the region that binds GDF11. Functional assays demonstrated a significant impact of the specific mutated amino acids on FST and GDF11 function and, together with embryonic expression data, provide strong evidence for the importance of GDF11 and Follistatin in the regulation of human orofacial development.

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Section: Discussionsupporting

confidence: 62%

Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans

Cox

Lidral²,

McCoy

et al. 2019

Human Mutation

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“…In the absence of Irf6 , mice exhibit severe cutaneous, limb, and orofacial defects and are perinatal lethal . Salivary glands and dental development are also altered in these mice, supporting a major role for IRF6 in craniofacial development. In humans, mutations in IRF6 cause Van der Woude syndrome (VWS, OMIM 119300) and popliteal pterygium syndrome (PPS, OMIM 119500) .…”

Section: Introductionmentioning

confidence: 90%

Interferon regulatory factor 6 is required for proper wound healing in vivo

Rhea

Canady

et al. 2019

Developmental Dynamics

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Background Van der Woude syndrome (VWS) is the most common form of syndromic orofacial cleft caused predominantly by mutations in Interferon Regulatory Factor 6 (IRF6). We previously reported that individuals with VWS have increased risk of wound healing complications following cleft repair compared with individuals with nonsyndromic orofacial clefts (nonsyndromic cleft lip and palate—NSCLP). In vitro, absence of IRF6 leads to impaired keratinocyte migration and embryonic wound healing. However, there is currently no data on tissue repair in adult animals and cells with reduced levels of IRF6 like in VWS. Results Excisional wounds of Irf6+/− and wild‐type animals were analyzed 4 and 7 days post‐wounding. Although all wounds were reepithelialized after 7 days, the epidermal and wound volume of repaired wounds was larger in Irf6+/−. These data were supported by increased keratinocyte proliferation in the neoformed epidermis and a less mature granulation tissue with increased cytokine levels. This effect was not cell autonomous, as Irf6+/− neonatal keratinocytes in vitro did not exhibit defects in scratch wound closure or proliferation. Keratinocytes from individuals with VWS also migrated similarly to keratinocytes from NSCLP individuals. Conclusions These data support a role for IRF6 in wound healing by regulating keratinocyte proliferation, granulation tissue maturation, and cytokine levels.

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“…This hypothesis is based on the following: (1) In this study, we observed no or incomplete recombination with the EIIa‐Cre “deleter strain,” and with two other tissue specific Cre transgenes, including K14‐Cre‐ER (Vasioukhin, Degenstein, Wise, & Fuchs, ) and Tgfb3‐Cre (Yang, Li, & Kaartinen, ; data not shown). (2), A previous study used this Irf6 fl allele to examine the role of Irf6 in dental epithelium, using the Pitx2‐Cre transgene (Chu et al, ). While the Pitx2‐Cre driver was previously shown to be competent to knockout other genes in oral epithelium that were required for palatogenesis (He et al ., ; Xiong et al ., ) , and Irf6 function in oral epithelium is required for palatogenesis (Ingraham et al, ; Richardson, Dixon, Jiang, & Dixon, ), no pathology was observed during palatogenesis (Chu et al, ).…”

Section: Resultsmentioning

confidence: 99%

Generation and characterization of a conditional allele of Interferon Regulatory Factor 6

Smith

Kousa

Kinoshita

et al. 2017

Genesis

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Interferon Regulatory Factor 6 (IRF6) is a critical regulator of differentiation, proliferation and migration of keratinocytes. Mutations in IRF6 cause two autosomal dominant disorders characterized by cleft lip with or without cleft palate. In addition, DNA variation in IRF6 confers significant risk for non-syndromic cleft lip and palate. IRF6 is also implicated in adult onset development and disease processes, including mammary gland development and squamous cell carcinoma. Mice homozygous for a null allele of Irf6 die shortly after birth due to severe skin, limb, and craniofacial defects, thus impeding the study of gene function after birth. To circumvent this, a conditional allele of Irf6 was generated. To validate the functionality of the conditional allele, we used three “deleter” Cre strains: Gdf9-Cre, CAG-Cre, and Ella-Cre. When Cre expression was driven by the Gdf9-Cre or CAG-Cre transgenes, 100% recombination was observed as indicated by DNA genotyping and phenotyping. In contrast, use of the Ella-Cre transgenic line resulted in incomplete recombination, despite expression at the one-cell stage. In sum, we generated a novel tool to delete Irf6 in a tissue specific fashion, allowing for study of gene function past perinatal stages. However, recombination efficiency of this allele was dictated by the Cre-driver used.

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Full Spectrum of Postnatal Tooth Phenotypes in a Novel Irf6 Cleft Lip Model

Cited by 31 publications

References 40 publications

Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans

Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans

Interferon regulatory factor 6 is required for proper wound healing in vivo

Generation and characterization of a conditional allele of Interferon Regulatory Factor 6

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