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- Title
HES1 is a novel downstream modifier of the SHH-GLI3 Axis in the development of preaxial polydactyly.
- Authors
Sharma, Deepika; Mirando, Anthony J.; Leinroth, Abigail; Long, Jason T.; Karner, Courtney M.; Hilton, Matthew J.
- 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. Author summary: Sonic Hedgehog/GLI3 signaling is critical in regulating digit number, such that Gli3-deficiency results in additional digits and Shh-deficiency leads to digit number reductions. SHH/GLI3 signaling within the developing limb regulates numerous genes critical for proper autopod (hand/foot) development, however not all target genes are known to be truly important for digit formation. 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. We further propose a mechanistic model by which HES1 coordinates the expression of genes important for proper digit development. These findings establish HES1 as a critical downstream effector of SHH/GLI3 signaling in the development of PPD.
- Subjects
POLYDACTYLY; CHONDROGENESIS; CELL proliferation; CELL cycle; GENE expression; FINGERS
- Publication
PLoS Genetics, 2021, Vol 17, Issue 12, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1009982