Open AccessHES1 is a novel downstream modifier of the SHH-GLI3 Axis in the development of preaxial polydactyly
Author(s) -
Deepika Sharma,
Anthony J. Mirando,
Abigail Leinroth,
Jason T Long,
Courtney M. Karner,
Matthew J. Hilton
Publication year - 2021
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1009982
Subject(s) - gli3 , sonic hedgehog , biology , hes1 , gli2 , microbiology and biotechnology , smoothened , hedgehog signaling pathway , polydactyly , signal transduction , genetics , notch signaling pathway , gene , gene expression , repressor
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.