|
|
|
|
|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | ||||
First published online 5 January 2006
doi: 10.1242/dev.02212
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Institute of Signaling, Developmental Biology and Cancer Research, CNRS UMR 6543, Centre de Biochimie, Parc Valrose, 06108 Nice Cedex 02, France.
* Author for correspondence (e-mail: therond{at}unice.fr)
Accepted 14 November 2005
The Hedgehog morphogen is a major developmental regulator that acts at short and long range to direct cell fate decisions in invertebrate and vertebrate tissues. Hedgehog is the only known metazoan protein to possess a covalently linked cholesterol moiety. Although the role of the cholesterol group of Hedgehog remains unclear, it has been suggested to be dispensable for the its long-range activity in Drosophila. Here, we provide data in three different epithelia - ventral and dorsal embryonic ectoderm, and larval imaginal disc tissue - showing that cholesterol modification is in fact necessary for the controlled long-range activity of Drosophila Hedgehog. We provide an explanation for the discrepancy between our results and previous reports by showing that unmodified Hh can act at long range, albeit in an uncontrolled manner, only when expressed in squamous cells. Our data show that cholesterol modification controls long-range Hh activity at multiple levels. First, cholesterol increases the affinity of Hh for the plasma membrane, and consequently enhances its apparent intrinsic activity, both in vitro and in vivo. In addition, multimerisation of active Hh requires the presence of cholesterol. These multimers are correlated with the assembly of Hh into apically located, large punctate structures present in active Hh gradients in vivo. By comparing the activity of cholesterol-modified Hh in columnar epithelial cells and peripodial squamous cells, we show that epithelial cells provide the machinery necessary for the controlled planar movement of Hh, thereby preventing the unrestricted spreading of the protein within the three-dimensional space of the epithelium. We conclude that, as in vertebrates, cholesterol modification is essential for controlled long-range Hh signalling in Drosophila.
Key words: Hedgehog morphogen, Cholesterol, Activity, Epithelia, Drosophila
Related articles in Development:
This article has been cited by other articles:
|
|
 |
|
  N. A. Thomas, M. Koudijs, F. J. M. van Eeden, A. L. Joyner, and D. Yelon Hedgehog signaling plays a cell-autonomous role in maximizing cardiac developmental potential Development, November 15, 2008; 135(22): 3789 - 3799. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Varjosalo and J. Taipale Hedgehog: functions and mechanisms Genes & Dev., September 15, 2008; 22(18): 2454 - 2472. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Buglino and M. D. Resh Hhat Is a Palmitoylacyltransferase with Specificity for N-Palmitoylation of Sonic Hedgehog J. Biol. Chem., August 8, 2008; 283(32): 22076 - 22088. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. F. Farzan, S. Singh, N. S. Schilling, and D. J. Robbins The Adventures of Sonic Hedgehog in Development and Repair. III. Hedgehog processing and biological activity Am J Physiol Gastrointest Liver Physiol, April 1, 2008; 294(4): G844 - G849. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Casso, S. Liu, D. D. Iwaki, S. K. Ogden, and T. B. Kornberg A Screen for Modifiers of Hedgehog Signaling in Drosophila melanogaster Identifies swm and mts Genetics, March 1, 2008; 178(3): 1399 - 1413. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Callejo, J. Culi, and I. Guerrero Patched, the receptor of Hedgehog, is a lipoprotein receptor PNAS, January 22, 2008; 105(3): 912 - 917. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Huang, Y. Litingtung, and C. Chiang Region-specific requirement for cholesterol modification of sonic hedgehog in patterning the telencephalon and spinal cord Development, June 1, 2007; 134(11): 2095 - 2105. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Varjosalo and J. Taipale Hedgehog signaling J. Cell Sci., January 1, 2007; 120(1): 3 - 6. [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Resh Palmitoylation of Ligands, Receptors, and Intracellular Signaling Molecules Sci. Signal., October 31, 2006; 2006(359): re14 - re14. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Wendler, X. Franch-Marro, and J.-P. Vincent How does cholesterol affect the way Hedgehog works? Development, August 15, 2006; 133(16): 3055 - 3061. [Abstract] [Full Text] [PDF]
|
|
