HES1 is a novel downstream modifier of the SHH-GLI3 Axis in the development of preaxial polydactyly |
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| Authors: | Deepika Sharma Anthony J Mirando Abigail Leinroth Jason T Long Courtney M Karner Matthew J Hilton |
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| Institution: | 1. Department of Orthopedic Surgery, Duke University School of Medicine, Durham, North Carolina, United States of America;2. Department of Biomedical Genetics, University of Rochester School of Medicine, Rochester, New York, United States of America;3. Department of Cell Biology, Duke University, Durham, North Carolina, United States of America; Children’s Hospital of Philadelphia, UNITED STATES |
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| Abstract: | Sonic Hedgehog/GLI3 signaling is critical in regulating digit number, such that Gli3-deficiency results in polydactyly and Shh-deficiency leads to digit number reductions. SHH/GLI3 signaling regulates cell cycle factors controlling mesenchymal cell proliferation, while simultaneously regulating Grem1 to coordinate BMP-induced chondrogenesis. SHH/GLI3 signaling also coordinates the expression of additional genes, however their importance in digit formation remain unknown. Utilizing genetic and molecular approaches, we identified HES1 as a downstream modifier of the SHH/GLI signaling axis capable of inducing preaxial polydactyly (PPD), required for Gli3-deficient PPD, and capable of overcoming digit number constraints of Shh-deficiency. Our data indicate that HES1, a direct SHH/GLI signaling target, induces mesenchymal cell proliferation via suppression of Cdkn1b, while inhibiting chondrogenic genes and the anterior autopod boundary regulator, Pax9. These findings establish HES1 as a critical downstream effector of SHH/GLI3 signaling in the development of PPD. |
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