Youssef A Kousa1,2, Dina Moussa3, Brian C Schutte1,3,4. 1. Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan. 2. Pediatric Residency Program, Children's National Health System, Washington, DC. 3. Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan. 4. Department of Pediatrics and Human Development, Michigan State University, East Lansing, Michigan.
Abstract
BACKGROUND: Mutations in IRF6, CHUK (IKKA), and RIPK4 can lead to a disease spectrum that includes cutaneous, limb, and craniofacial malformations. Loss of these alleles in the mouse leads to perinatal lethality and severe cutaneous, limb, and craniofacial defects also. Genetic rescue in the mouse has been shown for Ikka and Ripk4. RESULTS: Here, we show partial genetic rescue of Irf6 knockout embryos using the KRT14 promoter to drive Irf6 expression in the basal epithelium. In contrast to Irf6 knockout embryos, rescue embryos survive the immediate perinatal period. Macroscopic examination reveals rescue of skin adhesions between the axial and appendicular skeleton. Unexpectedly, KRT14-driven Irf6 expression does not completely rescue orofacial clefting and adhesions between the palate and tongue, suggesting the importance of cell-autonomous IRF6 expression in periderm. Like knockout embryos, Irf6 rescue embryos also have persistent esophageal adhesions, which likely contribute to postnatal demise. CONCLUSIONS: Together, these data suggest that targeted expression of IRF6 can significantly reduce disease severity, but that a minimum level of Irf6 in both periderm and basal epithelial cells is necessary for orofacial development. Therefore, homologous human and mouse phenotypes are observed for IRF6, IKKA, and RIPK4. In this work, we show that altering the expression level of IRF6 dramatically modified this phenotype in utero. Developmental Dynamics 246:670-681, 2017.
BACKGROUND: Mutations in IRF6, CHUK (IKKA), and RIPK4 can lead to a disease spectrum that includes cutaneous, limb, and craniofacial malformations. Loss of these alleles in the mouse leads to perinatal lethality and severe cutaneous, limb, and craniofacial defects also. Genetic rescue in the mouse has been shown for Ikka and Ripk4. RESULTS: Here, we show partial genetic rescue of Irf6 knockout embryos using the KRT14 promoter to drive Irf6 expression in the basal epithelium. In contrast to Irf6 knockout embryos, rescue embryos survive the immediate perinatal period. Macroscopic examination reveals rescue of skin adhesions between the axial and appendicular skeleton. Unexpectedly, KRT14-driven Irf6 expression does not completely rescue orofacial clefting and adhesions between the palate and tongue, suggesting the importance of cell-autonomous IRF6 expression in periderm. Like knockout embryos, Irf6 rescue embryos also have persistent esophageal adhesions, which likely contribute to postnatal demise. CONCLUSIONS: Together, these data suggest that targeted expression of IRF6 can significantly reduce disease severity, but that a minimum level of Irf6 in both periderm and basal epithelial cells is necessary for orofacial development. Therefore, homologous human and mouse phenotypes are observed for IRF6, IKKA, and RIPK4. In this work, we show that altering the expression level of IRF6 dramatically modified this phenotype in utero. Developmental Dynamics 246:670-681, 2017.
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Authors: Steven Goudy; Peggi Angel; Britni Jacobs; Cynthia Hill; Veronica Mainini; Arianna L Smith; Youssef A Kousa; Richard Caprioli; Lawrence S Prince; Scott Baldwin; Brian C Schutte Journal: PLoS One Date: 2013-02-22 Impact factor: 3.240
Authors: Fedik Rahimov; Mary L Marazita; Axel Visel; Margaret E Cooper; Michael J Hitchler; Michele Rubini; Frederick E Domann; Manika Govil; Kaare Christensen; Camille Bille; Mads Melbye; Astanand Jugessur; Rolv T Lie; Allen J Wilcox; David R Fitzpatrick; Eric D Green; Peter A Mossey; Julian Little; Regine P Steegers-Theunissen; Len A Pennacchio; Brian C Schutte; Jeffrey C Murray Journal: Nat Genet Date: 2008-10-05 Impact factor: 38.330
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Authors: Everett G Hall; Luke W Wenger; Nathan R Wilson; Sraavya S Undurty-Akella; Jennifer Standley; Eno-Abasi Augustine-Akpan; Youssef A Kousa; Diana S Acevedo; Jeremy P Goering; Lenore Pitstick; Nagato Natsume; Shahnawaz M Paroya; Tamara D Busch; Masaaki Ito; Akihiro Mori; Hideto Imura; Laura E Schultz-Rogers; Eric W Klee; Dusica Babovic-Vuksanovic; Sarah A Kroc; Wasiu L Adeyemo; Mekonen A Eshete; Bryan C Bjork; Satoshi Suzuki; Jeffrey C Murray; Brian C Schutte; Azeez Butali; Irfan Saadi Journal: Hum Mol Genet Date: 2020-03-27 Impact factor: 5.121
Authors: Shannon H Carroll; Claudio Macias Trevino; Edward B Li; Kenta Kawasaki; Nikita Myers; Shawn A Hallett; Nora Alhazmi; Justin Cotney; Russ P Carstens; Eric C Liao Journal: Development Date: 2020-12-23 Impact factor: 6.862