HES1 is a novel downstream modifier of the SHH-GLI3 Axis in the development of preaxial polydactyly.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Sharma, D; Mirando, AJ; Leinroth, A; Long, JT; Karner, CM; Hilton, MJ

Published Date

  • December 2021

Published In

Volume / Issue

  • 17 / 12

Start / End Page

  • e1009982 -

PubMed ID

  • 34928956

Pubmed Central ID

  • PMC8726490

Electronic International Standard Serial Number (EISSN)

  • 1553-7404

Digital Object Identifier (DOI)

  • 10.1371/journal.pgen.1009982


  • eng

Conference Location

  • United States