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.
Highlights
Development of the vertebrate limb is dependent on two signaling centers, the apical ectodermal ridge (AER) that controls proximal-distal (P-D) outgrowth and the zone of polarizing activity (ZPA), the source of Sonic hedgehog (Shh), which regulates anterior-posterior (A-P) patterning, digit number, and identity[1,2,3,4]
Sonic Hedgehog/GLI3 signaling is critical in regulating digit number, such that Gli family zinc finger 3 (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 development, not all target genes are known to be truly important for digit formation
Summary
Development of the vertebrate limb is dependent on two signaling centers, the apical ectodermal ridge (AER) that controls proximal-distal (P-D) outgrowth and the zone of polarizing activity (ZPA), the source of Sonic hedgehog (Shh), which regulates anterior-posterior (A-P) patterning, digit number, and identity[1,2,3,4]. GLI3 restricts the expression of Heart and neural crest derivatives-expressed protein 2 (Hand2) to the posterior mesenchyme, while HAND2 antagonizes Gli and Alx expression[5] This antagonistic relationship pre-patterns the mesenchyme allowing for the initiation of Shh within the posterior mesenchyme via the action of Fibroblast Growth Factors (FGFs) secreted from the AER [6,7]. A primary function of SHH within the autopod is to counteract the GLI3R-mediated constraints on digit development, and this dominance of GLI3R-mediated regulation of digit number and identity is highlighted by the indistinguishable forms of polydactyly observed in Gli3xt/xt mutant and Shh-/-; Gli3xt/xt compound mutant mice[15,16]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
