Trofka, A. | Search bioRxiv

bioRxiv2020

Sonic Hedgehog is not a limb morphogen but acts as a trigger to specify all digits.

Limb patterning by Sonic hedgehog (Shh) has served as a paradigm of "morphogen" function, acting either by graded spatial or temporal signal integration. Yet how Shh instructs distinct digit identities remains controversial. Here, we bypassed the requirement for Shh in cell survival during limb bud outgrowth and demonstrate that a transient, early Shh pulse is both necessary and sufficient for normal limb development. Our analysis of Shh-responding cells shows signaling acts at only short-range during this time window and that Shh patterns digits indirectly, via a relay mechanism, rather than by direct spatial or temporal signal integration. Using a genetic assay for relay signaling, we unexpectedly discovered Shh also specifies digit 1 (the thumb; previously thought to be exclusively Shh-independent) indirectly, thus implicating Shh in a unique regulatory hierarchy for digit 1 evolutionary adaptations, such as opposable thumbs. This study illuminates Shh as a trigger for a relay network that becomes rapidly self-sustaining, with mechanistic relevance for limb development, regeneration, and evolution.

developmental biology↗

bioRxiv2018

Mutual transcriptional repression between Gli3 and Hox13 genes determines the anterior-posterior asymmetry of the autopod

In the present study we have investigated the molecular causes of the absence of digit 1 in the Hoxa13 mutant and why the absence of Hoxa13 protein, whose expression spans the entire autopod, specifically impacts the anterior-most digit. We show that in the absence of Hoxa13, the expression of Hoxd13 does not extend into the anterior mesoderm consequently leaving the presumptive territory of digit1 devoid of distal Hox expression and providing an explanation for the agenesis of digit 1. We provide compelling evidence that the lack of Hoxd13 transcription in the anterior mesoderm is due to increased Gli3R activity, in turn resulting from the loss of transcriptional repression exerted by Hoxa13 on Gli3. Our results are compatible with a mutual transcriptional repression between Gli3 and Hox13 genes that determines the anterior-posterior asymmetry of the autopod.

developmental biology↗