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SHH\/GLI3 signaling regulates cell cycle factors controlling mesenchymal cell proliferation, while simultaneously regulating<jats:italic>Grem1<\/jats:italic>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<jats:italic>Cdkn1b<\/jats:italic>, while inhibiting chondrogenic genes and the anterior autopod boundary regulator,<jats:italic>Pax9<\/jats:italic>. These findings establish HES1 as a critical downstream effector of SHH\/GLI3 signaling in the development of PPD.<\/jats:p>","DOI":"10.1371\/journal.pgen.1009982","type":"journal-article","created":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T18:59:01Z","timestamp":1640026741000},"page":"e1009982","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["HES1 is a novel downstream modifier of the SHH-GLI3 Axis in the development of preaxial polydactyly"],"prefix":"10.1371","volume":"17","author":[{"given":"Deepika","family":"Sharma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9536-5528","authenticated-orcid":true,"given":"Anthony 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