Susan Mackem, MD, PhD
Senior Investigator, Cancer and Developmental Biology Laboratory
Center for Cancer Research
National Cancer Institute

Dr. Mackem received her PhD as an MSTP trainee from the U. of Chicago, her MD from Johns Hopkins U. School of Medicine, and residency training in Pathology at the National Cancer Institute, where she is currently a Senior Investigator (Cancer and Developmental Biology Lab., NCI-Frederick).  Her lab studies limb development as a model for learning how signaling networks orchestrate the formation of a complex 3-D structure, using combined genetic, genomic, and biochemical approaches to uncover the regulatory hierarchy between early patterning and final structure during digit morphogenesis.   A major focus has been the role of Sonic Hedgehog (Shh) and its main signaling targets, which together regulate the late morphogenetic realization of early patterning cues triggered by Shh.

Although proposed to act as a morphogen, how Shh instructs digit identity is still poorly understood.  We recently showed Shh acts only transiently, as a trigger, to specify a normal limb with all 5 digits.  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.  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 newly 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.