Multiple roles for lipids in the Hedgehog signalling pathway

Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
Nature Reviews Molecular Cell Biology (Impact Factor: 37.81). 07/2008; 9(6):437-45. DOI: 10.1038/nrm2414
Source: PubMed

ABSTRACT

The identification of endogenous sterol derivatives that modulate the Hedgehog (Hh) signalling pathway has begun to suggest testable hypotheses for the cellular biological functions of Patched, and for the lipoprotein association of Hh. Progress in the field of intracellular sterol trafficking has emphasized how tightly the distribution of intracellular sterol is controlled, and suggests that the synthesis of sterol derivatives can be influenced by specific sterol-delivery pathways. The combination of this field with Hh studies will rapidly give us a more sophisticated understanding of both the Hh signal-transduction pathway and the cell biology of sterol metabolism.

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Available from: Suzanne Eaton
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    • "A key question in the study of Hh signal transduction concerns the physiological mechanisms that influence Smo activity in pathway-responsive cells. One leading model hypothesizes that Smo is regulated by an endogenous lipidic modulator whose availability is controlled by Ptch1 transport activity (Eaton, 2008; Hausmann et al., 2009; Taipale et al., 2002). Indeed, a remarkable array of exogenous small molecules impinges on vertebrate Smo, including the plant-derived sterol cyclopamine and its synthetic mimics (Chen et al., 2002a, 2002b), which are finding therapeutic uses as pathway antagonists (Von Hoff et al., 2009; Rudin et al., 2009; Tang et al., 2012; Teglund and Toftgå rd, 2010). "
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    ABSTRACT: Hedgehog (Hh) signaling during development and in postembryonic tissues requires activation of the 7TM oncoprotein Smoothened (Smo) by mechanisms that may involve endogenous lipidic modulators. Exogenous Smo ligands previously identified include the plant sterol cyclopamine (and its therapeutically useful synthetic mimics) and hydroxylated cholesterol derivatives (oxysterols); Smo is also highly sensitive to cellular sterol levels. The relationships between these effects are unclear because the relevant Smo structural determinants are unknown. We identify the conserved extracellular cysteine-rich domain (CRD) as the site of action for oxysterols on Smo, involving residues structurally analogous to those contacting the Wnt lipid adduct in the homologous Frizzled CRD; this modulatory effect is distinct from that of cyclopamine mimics, from Hh-mediated regulation, and from the permissive action of cellular sterol pools. These results imply that Hh pathway activity is sensitive to lipid binding at several Smo sites, suggesting mechanisms for tuning by multiple physiological inputs.
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    • "The presence of the RND domain of Ptc1 further suggests that the pH of the cellular compartments is also important. Thus, intracellular lipid trafficking appears to be a key link between Ptc and Smo (Eaton, 2008). Incorporating these data lead to a model where Ptc1 activity constitutively prevents the activation of Smo by either keeping the net levels of positively acting oxysterols low or increasing the overall ratio of negative to positive sterols. "
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    ABSTRACT: Sonic Hedgehog (Shh) is one of three mammalian orthologs of the Hedgehog (Hh) family of secreted proteins first identified for their role in patterning the Drosophila embryo. In this review, we will highlight some of the outstanding questions regarding how Shh signaling controls embryonic development. We will mainly consider its role in the developing mammalian central nervous system (CNS) where the pathway plays a critical role in orchestrating the specification of distinct cell fates within ventral regions, a process of exquisite complexity that is necessary for the proper wiring and hence function of the mature system. Embryonic development is a process that plays out in both the spatial and the temporal dimensions, and it is becoming increasingly clear that our understanding of Shh signaling in the CNS is grounded in an appreciation for the dynamic nature of this process. In addition, any consideration of Hh signaling must by necessity include a consideration of data from many different model organisms and systems. In many cases, the extent to which insights gained from these studies are applicable to the CNS remains to be determined, yet they provide a strong framework in which to explore its role in CNS development. We will also discuss how Shh controls cell fate diversification through the regulation of patterned target gene expression in the spinal cord, a region where our understanding of the morphogenetic action of graded Shh signaling is perhaps the furthest advanced.
    Full-text · Article · Dec 2011 · Current Topics in Developmental Biology
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    • "In order to act on cells at a distance from the producing cell, these signaling molecules have to move through a hydrophilic environment. Formation of oligomers (B) and lipoprotein particles (C) are thought to mask hydrophobic residues or modifications and have been implicated in the transport of hydrophobic signals such as Hh and Wg. Figure modified from (Eaton 2008). "
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    ABSTRACT: Extracellular signaling molecules have crucial roles in development and homeostasis, and their incorrect deployment can lead to developmental defects and disease states. Signaling molecules are released from sending cells, travel to target cells, and act over length scales of several orders of magnitude, from morphogen-mediated patterning of small developmental fields to hormonal signaling throughout the organism. We discuss how signals are modified and assembled for transport, which routes they take to reach their targets, and how their range is affected by mobility and stability.
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