Hedgehogs like it sweet, too

In this issue of PNAS, Leahy and coworkers (1) present the first crystal structure of a complex between the N-terminal fragment of Hh (HhN) and an Ihog fragment encompassing its two extracellular fibronectin domains (IhogFn1–2). This work is part of the group's ongoing effort to elucidate the structural basis for hedgehog (Hh) signal transmission at the cell surface (2). Based on this structure and supporting biochemical data, the authors put forth a new model in which heparan sulfate glycosaminoglycans (HSGAGs) play a direct role in promoting Hh signaling.

Hh is a major morphogen during embryogenesis and is also involved in the maintenance of adult stem cells (3). The Hh pathway subtly controls transcription through a positive regulator, CiA, and a negative regulator, CiR (reviewed in ref. 4). Depending on the balance of those two transcription factors, Hh target genes may be activated, repressed, or responsive to regulation by other signaling pathways. This intricate system of transcriptional control enables the establishment of gradients at critical junctures in development, such as during the patterning of the anterior–posterior axis in fruit flies. Deregulated Hh signaling has been implicated in basal-cell carcinoma and medulloblastoma cancers (reviewed in ref. 5). To signal, Hh binds to Patched (Ptc) and releases Ptc's inhibition of Smoothened (Smo) (reviewed in ref. 6), allowing Smo to derepress transcription. Ihog is a recently discovered component of the cell surface Hh signaling apparatus that is necessary for high-affinity binding between Ptc and Hh …

*To whom correspondence should be addressed. E-mail: mohammad{at}saturn.med.nyu.edu