Control of signaling molecule range during developmental patterning

Cell. Mol. Life Sci. (2017) 74:1937–1956 DOI 10.1007/s00018-016-2433-5 Cellular and Molecular Life Sciences REVIEW Control of signaling molecule range during developmental patterning Scott G. Wilcockson1 • Catherine Sutcliffe1 • Hilary L. Ashe1 Received: 7 September 2016 / Revised: 24 November 2016 / Accepted: 5 December 2016 / Published online: 20 December 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Tissue patterning, through the concerted activity of a small number of signaling pathways, is critical to embryonic development. While patterning can involve signaling between neighbouring cells, in other contexts signals act over greater distances by traversing complex cellular landscapes to instruct the fate of distant cells. In this review, we explore different strategies adopted by cells to modulate signaling molecule range to allow correct patterning. We describe mechanisms for restricting signaling range and highlight how such short-range signaling can be exploited to not only control the fate of adjacent cells, but also to generate graded signaling within a field of cells. Other strategies include modulation of signaling molecule action by tissue architectural properties and the use of cellular membranous structures, such as signaling filopodia and exosomes, to actively deliver signaling ligands to target cells. Signaling filopodia can also be deployed to reach out and collect particular signals, thereby precisely controlling their site of action. Keywords Hh
Wnt
BMP
Dpp
Wg
FGF
Signaling
Cytoneme
stem cell
Embryo
Nodal ECM
Tissue architecture
HSPG & Hilary L. Ashe 1 Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK Introduction The ability to pattern fields of cells into distinct fates underpins multicellularity. Classical embryology experiments dating back to the early 1900s initially gave rise to the ideas of cell fate induction by other cells or tissues and the existence of gradients of substances that could generate pattern [1, 2]. Spemann and Mangold’s classic experiment revealed that tissue from the dorsal pole of a salamander embryo could induce a secondary axis when transplanted into a recipient embryo, giving rise to the principle of an ‘organizer’ [3]. The term morphogen, or ‘‘form producer’’, was then later coined by Turing who generated a model to explain how the reaction between these morphogens and their diffusion can generate biological pattern based on their differing concentrations at distinct positions [4]. Various ideas were proposed to explain morphogen gradient establishment and interpretation, including Crick’s source-sink model, whereby localized morphogen production is opposed by distant cells that act as a sink to destroy the morphogen [5], and Gierer and Meinhardt’s activatorinhibitor model, which combines a local self-enhancing activator with a long-range inhibitor activity [6]. Studies such as these offered explanations for the biology that underpins Wolpert’s theory of positional information and interpretation of morphogen concentrations in classical French Flag-type responses [7, 8]. However, it was not until the late 1980s that molecular and genetic studies in Drosophila finally enabled the visualization and manipulation of the graded Bicoid and Dorsal proteins that pattern cell fates along the anterior–posterior and dorsal–ventral axes, respectively [9–12]. Although these two gradients are unusual in that they exist in the syncytial embryo, further studies have provided evidence for the gradients of extracellular signals, first for the Bone Morphogenetic Protein 123 1938 (BMP) homologue Decapentaplegic (Dpp) in the Drosophila wing and embryo, and gradients of all major classes of signals have now been described [1]. While the simplest mechanism for regulating signaling range is diffusion of a signaling molecule from its source, studies in many contexts have revealed more elaborate mechanisms. In this review, we highlight common themes that have emerged in relation to signaling molecule distribution based on recent studies of different types of signaling molecules in diverse contexts. Short-range signaling In this section, we describe different mechanisms used to generate short-range signaling, showing how local signaling can generate pattern either across a single cell diameter or even within a cellular field. Restriction of Dpp diffusion by receptors and co-receptors The Drosophila ovary is a bundle of *15 ovarioles, with a germarium structure at the anterior tip of each ovariole. Within the germarium, typically two germline stem cells (GSCs) reside within a niche comprised of somatic cells (Fig. 1a). Upon GSC division, one cell remains as a GSC, while the other daughter exits the niche and differentiates into a cystoblast [13]. Dpp, likely as a Dpp-Glass bottom boat (Gbb) heterodimer, functions as a self-renewal signal acting at exquisitely short-range over only one cell diameter [14]. In this context, the activities of receptors and co-receptors are used to regulate Dpp range and, therefore, GSC number. Glypicans are a family of heparin sulfate proteoglycans (HSPGs), bound to the outer surface of the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor [15]. The Drosophila glypican Division abnormally delayed (Dally) is expressed by niche cap cells and acts within the somatic niche to promote short-range Dpp signaling within GSCs [16, 17] (Fig. 1a). Dally function is limited to cap cells due to repression of dally transcription in escort cells (ECs) and escort stem cells that lie posterior to the niche and enclose the germline cells. dally repression in these cells is mediated by EGF signaling, with EGF ligands released by germline cells, including GSCs [18]. Removal of Dally from cap cells leads to a loss of GSCs due to differentiation as a result of reduced Dpp signaling, whereas misexpression of dally in ECs increases GSC number [16, 17]. In the germarium, Dally function depends on it being membrane localized [16]. Dally binds Dpp [19] and promotes short-range Dpp signaling potentially by concentrating or stabilizing Dpp at the niche, increasing GSC sensitivity to Dpp [16, 17], and/or by acting as a Dpp 123 S. G. Wilcockson et al. trans co-receptor, which would limit efficient Dpp signaling to the niche area where Dally on cap cells and BMP receptors on GSCs coincide [17]. It has been proposed that the design of dally expression and presentation by niche cells, rather than by GSCs, may facilitate the required loss of Dpp signaling upon cells exiting the niche [16]. In contrast, if the GSCs were to express dally, Dpp could remain associated with the cell upon division, which is not compatible with the sharp on–off distinction in Dpp signaling required for the GSC-CB fate change. In the wing disc, Dally is antagonised by the secreted protein Pentagone (Pent), via an interaction that le (...truncated)