Cell
Volume 105, Issue 5, 1 June 2001, Pages 599-612
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Article
Cholesterol Modification of Sonic Hedgehog Is Required for Long-Range Signaling Activity and Effective Modulation of Signaling by Ptc1

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Abstract

Sonic hedgehog (Shh) signaling from the posterior zone of polarizing activity (ZPA) is the primary determinant of anterior-posterior polarity in the vertebrate limb field. An active signal is produced by an autoprocessing reaction that covalently links cholesterol to the N-terminal signaling moiety (N-Shhp), tethering N-Shhp to the cell membrane. We have addressed the role played by this lipophilic modification in Shh-mediated patterning of mouse digits. Both the distribution and activity of N-Shhp indicate that N-Shhp acts directly over a few hundred microns. In contrast, N-Shh, a form that lacks cholesterol, retains similar biological activity to N-Shhp, but signaling is posteriorly restricted. Thus, cholesterol modification is essential for the normal range of signaling. It also appears to be necessary for appropriate modulation of signaling by the Shh receptor, Ptc1.

Cited by (0)

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Present address: Division of Developmental Biology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA.

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Present address: Alkek Institute of Biosciences and Technology, Texas A&M System Health Science Center, 2121 Holcombe Boulevard, Houston, Texas 77030.

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Present address: Curis, 64 Moulton Street, Cambridge, Massachusetts 02138.