Elife 2020 Oct 2; 9:e56450
Despite a common understanding that Gli TFs are utilized to convey a Hh morphogen gradient, genetic analyses suggest craniofacial development does not completely fit this paradigm. Using the mouse model (Mus musculus), we demonstrated that rather than being driven by a Hh threshold, robust Gli3 transcriptional activity during skeletal and glossal development required interaction with the basic helix-loop-helix TF Hand2. Not only did genetic and expression data support a co-factorial relationship, but genomic analysis revealed that Gli3 and Hand2 were enriched at regulatory elements for genes essential for mandibular patterning and development. Interestingly, motif analysis at sites co-occupied by Gli3 and Hand2 uncovered mandibular-specific, low-affinity, 'divergent' Gli-binding motifs (dGBMs). Functional validation revealed these dGBMs conveyed synergistic activation of Gli targets essential for mandibular patterning and development. In summary, this work elucidates a novel, sequence-dependent mechanism for Gli transcriptional activity within the craniofacial complex that is independent of a graded Hh signal.
Elliott, Kelsey H; Chen, Xiaoting; Salomone, Joseph; Chaturvedi, Praneet; Schultz, Preston A; Balchand, Sai K; Servetas, Jeffrey D; Zuniga, Aimée; Zeller, Rolf; Gebelein, Brian; Weirauch, Matthew T; Peterson, Kevin A; and Brugmann, Samantha A, "Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks." (2020). Faculty Research 2020. 209.