Regulation of the Hedgehog Morphogene Gradient
The development of a multicellular organism is controlled by a genetic program that manifests itself in proliferation, cell differentiation, and apoptosis, leading to the formation of functional organs. A small number of secreted molecules work as “instru
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Regulation of the Hedgehog Morphogene Gradient* G. D’Angelo, F. Wendler, K. Ayers, and P. P. Thérond
Keywords Hedgehog • Secretion • Trafficking • Morphogenetic gradient • Extracellular matrix • Heparan sulfate proteoglycans
Introduction The development of a multicellular organism is controlled by a genetic program that manifests itself in proliferation, cell differentiation, and apoptosis, leading to the formation of functional organs. A small number of secreted molecules work as “instructors” during these processes [1, 2]. Among them are the Hedgehog (Hh) family of proteins, which act from their source of production at short and long range. They trigger cell fate decisions by inducing a signaling cascade in the ligandreceiving tissues of invertebrates and vertebrates. Dramatic developmental abnormalities are observed in human embryos with compromised Hh signaling, and while great effort is being made to understand and manipulate the signaling cascade downstream of Hh receptor activation, less attention has been payed to the secretion and release of the Hh ligand itself. In this review, we will discuss recent progresses in the understanding of Hh ligand packaging and dispatch from producing cells and its consequences for gradient formation.
* The first two authors contributed equally to this manuscript. P.P. Thérond (*) Institut Biologie du Développement & Cancer – IBDC, Université de Nice Sophia-Antipolis, UMR6543 CNRS, Centre de Biochimie, Parc Valrose, 06108 Nice cedex 2, France e-mail: [email protected] J. Xie (ed.), Hedgehog Signaling Activation in Human Cancer and its Clinical Implications, DOI 10.1007/978-1-4419-8435-7_2, © Springer Science+Business Media, LLC 2011
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Atypical Biosynthesis of Active Hh Signaling Peptide An evolutionarily conserved feature of Hh family proteins resides in their hydrophobic lipid modifications. Immature Hh protein enters the secretory pathway where proteolytic autoprocessing and lipidation produce an N-terminal active Hh peptide modified on the C-terminus by a cholesterol moiety, both on Drosophila Hh and on its vertebrate counterpart Sonic Hedgehog (Shh) [3] (Fig. 2.1). Moreover, active Hh is also modified by the attachment of a stable amide-linked palmitic acid at the opposing N-terminal end [4, 5]. This acylation is catalyzed by the Skinny Hedgehog protein (Skn or Ski, also called Rasp, Central missing and Sightless) [5–8] that belongs to the family of membrane bound O-acyl-tranferases (MBOAT) [9]. The importance of these dual lipid modifications is underscored by the fact that removal of these modifications interferes with the biological activity of Hh in vivo. Notably, mutations that affect the human Shh autocatalytic processing are associated with holoprosencephaly [10].
Routing of Hh to the Plasma Membrane The presence of lipid moieties has a significant effect on Hh solubility and is, therefore, bound to affect intracellular trafficking to the plasma membrane in producing cells. Strikingly, although Hh lipidation is essential for its act
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