Harvard University - Department of Molecular & Cellular Biology

CLUES TO SONIC HEDGEHOG'S BEHAVIOR

by Andrew McMahon

May 10th, 2006


Co-authors Andy McMahon, Toyo Tenzen and Benjamin Allen
The Hedgehog signaling pathway has emerged as a key regulator of normal embryonic development and a major contributor to a spectrum of cancers. A recent report from Toyo Tenzen and Benjamin Allen, postdoctoral scientists in the McMahon group in MCB, identifies two new components of this pathway that ensure the appropriate outcome to Hedgehog signals in their target tissues. The findings have been published in the May 9th issue of Developmental Cell (Tenzen et al.).

Sonic hedgehog, the best-studied member of the mammalian Hedgehog family, is critical for the specification of all ventral neuronal identities in the mammalian central nervous system. In the early embryo, Sonic hedgehog acts as a morphogen to induce different classes of neural progenitors–for example, motor neurons responsible for control of muscle contraction–at distinct concentrations of the signal. The new work from the McMahon group, a collaboration with scientists at Mount Sinai Hospital in New York, demonstrates that Sonic hedgehog signaling is aided in this morphogenesis by binding to cell surface proteins, Cdo and Boc, previously associated with muscle differentiation. Intriguingly, both genes are themselves negatively regulated by Hedgehog signaling in most Hedgehog-responsive cell types, except those that require the highest level of signaling. The data support a model where Cdo or Boc binding to Sonic hedgehog may ensure robust high level signaling where a maximal response is required and also at the fringes of the target field were signal levels are very low. Molecular dissection of the Cdo and Boc proteins maps their binding activity to a single repeat structure in the extracellular domain.

Two concurrent reports (Yao et al. Cell. 2006. Apr 21;125(2):343-57) and Zhang et al also in the May 9 issue of Developmental Cell indicate similar roles for Cdo/Boc, and related factors, in the mammalian and fruit fly Hedgehog pathway, and point to a potential role for Cdo activity in the modulation of holoprosencephaly, a devastating midline disorder linked to Hedgehog mediated patterning of the brain and face.  A mini-review in Cell by C. W. Wilson and P.-T. Chuang (May 5, 125 (3), 435-438) offers a perspective on the findings.