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ScienceWeek
MOLECULAR BIOLOGY: ON HEDGEHOG PROTEINS
The following points are made by L. Lum and P.A. Beachy (Science 2004 304:1755):
1) The expression and activity of Hedgehog proteins (Hh) exemplify a common strategy for pattern generation in metazoan embryos, namely, the specification of multiple cell fates through localized production and secretion of an instructive signal. In this manner, Hh signals regulate cell proliferation and differentiation in a diverse array of essential patterning events ranging from embryonic segmentation and appendage development in insects to neural tube differentiation in vertebrates (1).
2) However, Hh signaling also assumes homeostatic roles in postembryonic tissues to maintain stem cells (2-5), and continuous Hh pathway activity plays a pathological role in the growth of a group of endodermally derived human cancers that together account for 25% of human cancer deaths. Despite the importance of these processes in human health and disease, substantial gaps remain in our understanding of the mechanisms that mediate Hh signal response.
3) Hh proteins enter the secretory pathway and undergo autoprocessing and lipid modification reactions that produce a signaling peptide dually modified at its N- and C-termini by palmitoyl and cholesteryl adducts, respectively. Despite its dual lipid modification and consequent tight association with membranes, the Hh protein acts directly on distant cells in developing tissues. This remote action requires the transmembrane transporter-like protein Dispatched (Disp) for release of Hh from secreting cells, the heparan sulfate proteoglycans Dally-like (Dlp) and Dally for extracellular transport of Hh protein, and enzymes such as Sulfateless and Tout velu that are required for heparan sulfate biosynthesis.
4) Hh pathway activity is triggered by stoichiometric binding of Hh ligand to Patched (Ptc), also an apparent transmembrane transporter that in the absence of Hh acts catalytically to suppress activity of the seven-transmembrane protein Smoothened (Smo). Inactivation of Ptc by binding to Hh permits activation of Smo, which in turn results in activation of latent cytoplasmic transcription factors, the Ci protein in Drosophila and the homologous Gli proteins in mammals. These aspects of the Hh signal response circuitry are well established and widely conserved from insects to mammals. Many of these findings, however, have their basis in genetic studies, which do not provide a mechanistic understanding of how the Hh signal is sensed, how Ptc switches Smo activity off, and how activation is routed from Smo in the membrane to Ci or Gli in the cytoplasm.
5) In summary: The Hedgehog (Hh) signaling pathway is intimately linked to cell growth and differentiation, with normal roles in embryonic pattern formation and adult tissue homeostasis, and pathological roles in tumor initiation and growth. Recent advances in our understanding of Hh response have resulted from the identification of new pathway components and new mechanisms of action for old pathway components. The most striking new finding is that signal transmission from membrane to cytoplasm proceeds through recruitment, by the seven-transmembrane protein Smoothened, of an atypical kinesin, which routes pathway activation by interaction with other components of a complex that includes the latent zinc finger transcription factor, Ci.
References (abridged):
1. T. M. Jessell, Nat. Rev. Genet. 1, 20 (2000)
2. Y. Zhang, D. Kalderon, Nature 410, 599 (2001)
3. J. Taipale, P. A. Beachy, Nature 411, 349 (2001)
4. T. Reya, S. J. Morrison, M. F. Clarke, I. L. Weissman, Nature 414, 105 (2001)
5. R. Machold et al., Neuron 39, 937 (2003)
Science http://www.sciencemag.org
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Related Material:
ON HEDGEHOG PROTEINS
Notes by ScienceWeek:
A "hedgehog protein" is a transmembrane protein involved in segment polarity and cell-cell signaling during embryogenesis and metamorphosis in the fruit fly Drosophila melanogaster, and in other insects and vertebrates.
The following points are made by P.W. Ingham and A.P. McMahon (Genes & Development 2001 15:3059):
1) Since their isolation in the early 1990s, members of the hedgehog family of intercellular signaling proteins have come to be recognized as key mediators of many fundamental processes in embryonic development. The activities of these proteins are central to the growth, patterning, and morphogenesis of many different regions within the body plans of vertebrates and insects, and most likely other invertebrates. In some contexts, hedgehog signals act as morphogens in the dose-dependent induction of distinct cell fates within a target field, in others as mitogens regulating cell proliferation, or as inducing factors controlling the form of a developing organ. These diverse functions of hedgehog proteins raise many intriguing questions about their mode of operation. For example, how do these proteins move between or across fields of cells? How are their activities modulated or transduced? What are their intracellular targets?
2) Embryological studies over much of the last century that relied primarily on the physical manipulation of cells within the developing embryo or within fragments of the embryo in culture, provided many compelling examples of the primacy of cell-cell interactions in regulating invertebrate and vertebrate development. The subsequent identification of many of the signaling factors that mediate cellular communication has led to two general conclusions: a) Although there are many important signals, most of these fall into a few large families of secreted peptide factors. b) Parallel studies in invertebrate and vertebrate systems have demonstrated that although the final outcome might look quite different (e.g., a fly versus a mouse), there is a striking evolutionary conservation in the deployment of members of the same signaling families to regulate development of these seemingly quite different organisms. One of the most intriguing examples of this phenomenon is the hedgehog family of proteins.
Genes & Development http://www.genesdev.org
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Related Material:
ON BODY PATTERNING IN DEVELOPMENT
The following points are made by Y. Takahashi et al (Proc. Nat. Acad. Sci. 2001 98:12338):
1) Ontogenesis (the developmental processes of an individual animal) begins with a fertilized egg, and through proliferation, this single cell becomes a homogeneous mass of cells. This mass of cells then becomes subdivided into distinct groups that eventually will exhibit functional specialization later in development. If the units fail to be correctly established in time and space, certain specializations might be entirely missing from the embryo, or cells might randomly differentiate (specialize) in the wrong place. Furthermore, cells specializing in the wrong place may end up dying because they fail to be properly integrated with the rest of the organism. All of these outcomes can have dire effects on the body.
2) The progress of organogenesis is governed by patterning processes that have occurred earlier during development and that involve the action of cell-cell signaling pathways, growth factors acting between cells, and transcription factors acting within cells. In general, both body segmentation and brain patterning are essential for conferring a highly organized functional complexity to the body. In both cases, an originally homogeneous group of cells obtains characteristics to give rise to particular structures and functions in a precise spatial and temporal pattern. This produces patterns such as the regular repetition of skeletal elements and the 3-dimensional compartments of brain primordium on which the subsequent complexity of the neuronal network is organized. It is now widely accepted that similar sets of factors are shared by different animal species and also by distinct processes in the course of early patterning of organogenesis. During animal evolution, a "prepattern" of fundamental organs apparently emerged relatively early.
Proc. Nat. Acad. Sci. http://www.pnas.org
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