Differential Cellular Responses to Hedgehog Signalling in Vertebrates—What Is the Role of Competence?
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Journal of Developmental Biology Review Differential Cellular Responses to Hedgehog Signalling in Vertebrates—What is the Role of Competence? Clemens Kiecker 1,*, Anthony Graham 1 and Malcolm Logan 2 1 Department of Developmental Neurobiology, King’s College London, Hodgkin Building, Guy’s Hospital Campus, London SE1 1UL, UK; [email protected] 2 Randall Division of Cell & Molecular Biophysics, King’s College London, Hodgkin Building, Guy’s Hospital Campus, London SE1 1UL, UK; [email protected] * Correspondence: [email protected]; Tel.: +44-(0)20-7848-6546 Academic Editors: Henk Roelink and Simon J. Conway Received: 23 October 2016; Accepted: 1 December 2016; Published: 10 December 2016 Abstract: A surprisingly small number of signalling pathways generate a plethora of cellular responses ranging from the acquisition of multiple cell fates to proliferation, differentiation, morphogenesis and cell death. These diverse responses may be due to the dose-dependent activities of signalling factors, or to intrinsic differences in the response of cells to a given signal—a phenomenon called differential cellular competence. In this review, we focus on temporal and spatial differences in competence for Hedgehog (HH) signalling, a signalling pathway that is reiteratively employed in embryos and adult organisms. We discuss the upstream signals and mechanisms that may establish differential competence for HHs in a range of different tissues. We argue that the changing competence for HH signalling provides a four-dimensional framework for the interpretation of the signal that is essential for the emergence of functional anatomy. A number of diseases—including several types of cancer—are caused by malfunctions of the HH pathway. A better understanding of what provides differential competence for this signal may reveal HH-related disease mechanisms and equip us with more specific tools to manipulate HH signalling in the clinic. Keywords: chick embryo; Drosophila; iroquois; IRX; limb bud; morphogen; mouse; neural tube; proliferation; temporal adaptation; zebrafish 1. Introduction Classical embryologists postulated over 100 years ago that cells in a developing multicellular organism communicate with each other: some cells emit signals, inducers, that elicit specific changes in the receiving target cells. Around that time it was also recognised that the target cells need to be able to interpret the signal—they need to be competent [1,2]. Over the last 30 years, the rise of molecular biology has led to the identification of the signals that induce a multitude of cellular behaviours and identity changes during development. One of the biggest surprises from this research was that a small number of signalling pathways (less than a dozen) seem to direct not only the formation of the hundreds of different cell types that make up a functional organism, but they also regulate cellular proliferation, morphogenesis, motility and cell death. Moreover, the same signals are also active in adult homeostasis, and consequentially their deregulation can cause diseases such as cancer. J. Dev. Biol. 2016, 4, 36; doi:10.3390/jdb4040036 www.mdpi.com/journal/jdb J. Dev. Biol. 2016, 4, 36 2 of 22 J. Dev. ThisBiol. 2016 raises, 4, 36 the question of how a small number of signals can generate such a broad range2 of 22 of cellular responses. There are two—not necessarily mutually exclusive—possible answers to this question:This raises the question of how a small number of signals can generate such a broad range of cellular responses. There are two—not necessarily mutually exclusive—possible answers to this 1. Inducing signals may elicit multiple cellular responses in a dose-dependent fashion, question: i.e., they function as morphogens (Figure1A) [3]. 1. Inducing signals may elicit multiple cellular responses in a dose-dependent fashion, i.e., they 2. functionCellular as responses morphogens may depend(Figure 1A) on cell-intrinsic [3]. factors that reflect the context of the responding 2. Cellularcell, its locationresponses and may developmental depend on cell-intrinsic history (Figure factors1B). that This reflec contextualt the context ability of tothe respond responding to a cell,signal its bringslocation us and back developmental to the idea of cellularhistory competence:(Figure 1B). This cells contextual that respond ability differently to respond to a given to a signalsignal brings display usdifferential back to the competence idea of cellularfor this co signal.mpetence: cells that respond differently to a given signal display differential competence for this signal. Figure 1. Two scenarios for the induction of multiple cellular responses (blue, white, red) by a signalling Figure 1. Two scenarios for the induction of multiple cellular responses (blue, white, red) by a factor (green). (A) The factor acts as a morphogen that induces multiple responses dose-dependently; signalling factor (green). (A) The factor acts as a morphogen that induces multiple responses (B) A pre-pattern in the receiving cells (light green vs. brown) results in differential responses to the dose-dependently; (B) A pre-pattern in the receiving cells (light green vs. brown) results in signal—the receiving cells display differential competence. differential responses to the signal—the receiving cells display differential competence. InIn the the first first scenario, scenario, differential differential cellular cellular resp responsesonses are are determined determined by by different different doses doses of of the the inducer,inducer, aa nonnon cell-autonomous cell-autonomous factor. factor. In contrast,In contrast, differential differential competence competence can be can defined be defined as a property as a propertyinherent toinherent the responding to the responding cell that determines cell that howdetermines this cell how responds this cell to a responds given signal. to a Biologists given signal. have Biologistsmade tremendous have made progress tremendous in establishing progress in the establishing molecular mechanicsthe molecular of the mechanics signalling of pathwaysthe signalling that pathwaysunderlie cell-to-cell that underlie communication, cell-to-cell butcommunica our understandingtion, but ofour what understanding mediates differential of what competence mediates differentialis lagging behind. competence is lagging behind. InIn this this review, review, we we focus focus on on the the phenomenon phenomenon of of differential differential competence competence with with regards regards to to the the HedgehogHedgehog (HH) (HH) pathway—a pathway—a signalling signalling cascade cascade that that is is found found across across the the animal animal kingdom, kingdom, that that is is involvedinvolved in in multiple multiple processes processes during during embryogene embryogenesissis as as well well as as adult adult homeostasis, homeostasis, and and that that is is frequentlyfrequently defective defective in in different different types types of of cancers cancers and and other other diseases diseases.. We We begin begin by by providing providing a a brief brief outlineoutline of the HHHH pathwaypathway andand some some examples examples for for its its various various roles. roles. 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A Brief Outline of the Hedgehog Pathway Hh genes are found throughout the animal kingdom. Vertebrates have three hhs: Desert hedgehog (Dhh), Indian hedgehog (Ihh) and Sonic hedgehog (Shh), although Ihh and Shh have undergone J. Dev. Biol. 2016, 4, 36 3 of 22 2. A Brief Outline of the Hedgehog Pathway Hh genes are found throughout the animal kingdom. Vertebrates have three hhs: Desert hedgehog (Dhh), Indian hedgehog (Ihh) and Sonic hedgehog (Shh), although Ihh and Shh have undergone duplications in some teleosts [4]. The HH ligand is bound by a large multipass transmembrane protein called Patched (PTC). In the absence of HH, PTC inhibits the signalling activity of the seven-pass transmembrane protein Smoothened (SMO); however, once PTC has bound HH, this inhibition is relieved and SMO can trigger an intracellular signalling cascade. Initial studies suggesting that PTC and SMO form a physical complex have been refuted, as PTC was shown to inhibit SMO sub-stoichiometrically, indicating that a catalytic mechanism must be at work [5,6]. The structural similarity of PTC with small molecule transporters suggests that it could function by shuttling a small regulator of SMO across the cell membrane [7,8]. It is a common assumption that all cells of early vertebrate embryos express at least one of the two Ptc genes and Smo, at least at low levels,