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bioRxiv · 10.1101/2020.06.17.158501

HES1 is a critical mediator of the SHH-GLI3 axis in regulating digit number

Hilton, M. J.·Sharma, D.·Mirando, A. J.·Leinroth, A.·Long, J. T.·Karner, C. M.
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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. Anterior-posterior SHH/GLI3 signaling gradients regulate cell cycle factors controlling mesenchymal cell proliferation, while simultaneously regulating Grem1 to coordinate BMP-induced chondrogenesis. SHH/GLI3 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 key transcriptional regulator downstream of SHH/GLI signaling 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 fill gaps in knowledge regarding digit number and patterning, while creating a comprehensive framework for our molecular understanding of critical mediators of SHH/GLI3 signaling.

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Hilton, M. J., Sharma, D., Mirando, A. J., Leinroth, A., Long, J. T., Karner, C. M.. 2020-06-18. HES1 is a critical mediator of the SHH-GLI3 axis in regulating digit number. https://doi.org/10.1101/2020.06.17.158501

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