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Paul Scherz
Harvard Medical School
Department of Genetics
77 Avenue Louis Pasteur
Boston, MA

(617) 432-6531





Shh-descendants and patterning the vertebrate limb

The zone of polarizing activity in the posterior limb bud produces Sonic Hedgehog (Shh) protein which plays a critical role in establishing distinct fates along the anterior-posterior axis. This activity has been modeled as a concentration-dependent response to a diffusible morphogen, and indeed is the context in which the idea of a developmental morphogen was first articulated. We have used recombinase-base mapping in the mouse to determine the ultimate fate of the cells which produce the Shh signal. Strikingly, the descendants of the Shh-producing cells encompass all of cells in the two most posterior digits and also contribute to the middle digit. Our analysis suggests that it is the length of time exposure to Shh that specifies the differences between the most posterior digits and that only the more anterior digits are specified by the concentration of Shh. Genetic studies of the effects of limiting accessibility of Shh within the limb support this model where the effect of the Shh morphogen is dictated by a temporal, as well as, a spatial gradient. I am continuing to study the by reducing the levels of Shh in the limb at different timepoints using a Shh::Cre mouse, and cyclopamine in the chick limb.




I am also interested in the regulation of organ size.Vertebrate limb outgrowth is driven by a positive feedback loop involving Sonic Hedgehog (Shh), Gremlin, and Fgf4. By overexpressing individual components of the loop at a time after these genes are normally down-regulated in chicken embryos, we found that Shh no longer maintains Gremlin in the posterior limb. Shh-expressing cells and their descendants cannot express Gremlin. The proliferation of these descendants forms a barrier separating the Shh signal from Gremlin-expressing cells, which breaks down the Shh-Fgf4 loop and thereby affects limb size and provides a mechanism explaining regulative properties of the limb bud.