Senior Investigator, and Staff Anatomic Pathology Center for Cancer Research, NCI, NIH Frederick, Maryland, United States
The vertebrate limb, particularly the distal (hand) skeleton, is a major site for adaptive evolutionary modifications arising from developmental changes. The Sonic hedgehog (Shh) pathway is central to the regulatory network controlling morphogenesis (patterning) of different digit types. Although proposed to act as a morphogen, how Shh instructs digit identity is still poorly understood and we recently showed that Shh acts only transiently, as a trigger, to specify a normal limb with all 5 digits (Dev. Cell, 2022). In fact, digit identity is an emergent morphologic property not based in cell fate changes per se, implying ongoing downstream regulation, and we propose that Shh acts primarily to set up late signaling centers that orchestrate digit formation. In the course of this work we also found that both Shh expression and response are highly dynamic and suggest ongoing recruitment of new cells to become Shh-expressing, rather than expansion from a single population. Cells recruited to become Shh-expressing also become refractory to direct response, but resume responsiveness once they cease Shh expression. These features add a new dimension of Shh signaling "robustness" to genetic and environmental perturbation, beyond simple feedback mechanisms, and beg the question of why there is an apparent need for non-responsiveness in Shh-producing cells.
