Myosin 10 and a Cytoneme-Localized Ligand Complex Promote Morphogen Transport

Abstract

SummaryMorphogens function in concentration-dependent manners to instruct cell fate during tissue patterning. Molecular mechanisms by which these signaling gradients are established and reinforced remain enigmatic. The cytoneme transport model posits that specialized filopodia extend between morphogen-sending and responding cells to ensure that appropriate signal activation thresholds are achieved across developing tissues. How morphogens are transported along and deployed from cytonemes is not known. Herein we show that the actin motor Myosin 10 promotes cytoneme-based transport of Sonic Hedgehog (SHH) morphogen to filopodial tips, and that SHH movement within cytonemes occurs by vesicular transport. We demonstrate that cytoneme-mediated deposition of SHH onto receiving cells induces a rapid signal response, and that SHH cytonemes are promoted by a complex containing a ligand-specific deployment protein and associated co-receptor.One-Sentence summaryCytoneme-based delivery of the Sonic Hedgehog activation signal is promoted by Myosin 10 and BOC/CDON co-receptor function.

Hedgehog Pathway Activation Requires Coreceptor-Catalyzed, Lipid-Dependent Relay of the Sonic Hedgehog Ligand

“…The nature of the extracellular SHH species and the mechanism by which it moves between cells remain unclear (Petrov et al, 2017). Exosomes (Gradilla et al, 2014;Matusek et al, 2014), lipoprotein particles (Pana ´kova ´et al, 2005), and specialized signaling filopodia known as cytonemes (Ramı ´rez-Weber and Kornberg, 1999;Callejo et al, 2011;Bischoff et al, 2013;Chen et al, 2017;Hall et al, 2020) have all been proposed as possible carriers for extracellular SHH. However, whether or not such a carrier is involved, dually lipidated SHH must pass through an aqueous environment before reaching the surface of the target cell, a process likely requiring a solubilizing factor.…”

Competitive coordination of the dual roles of the Hedgehog co-receptor in homophilic adhesion and signal reception

“…Besides the wing imaginal disc epithelia, cytoneme-mediated Hh reception and transport have been described in other Drosophila tissues, such as the abdominal and the female germline stem cell niche ( Rojas-Ríos et al, 2012 ; Bischoff et al, 2013 ; González-Méndez et al, 2017 ). The involvement of cytonemes in Hh signaling has been extended from insect to vertebrates by studies of the limb bud of chick embryo and cultured mouse embryonic fibroblasts ( Sanders et al, 2013 ; Hall et al, 2020 ). The vertebrate homologs of the Drosophila Ihog proteins, Cdo and Boc, localize in cytonemes, and overexpression of either CDO or BOC increases the number of cytonemes detected on mammalian cells ( Hall et al, 2020 ).…”

“…The involvement of cytonemes in Hh signaling has been extended from insect to vertebrates by studies of the limb bud of chick embryo and cultured mouse embryonic fibroblasts ( Sanders et al, 2013 ; Hall et al, 2020 ). The vertebrate homologs of the Drosophila Ihog proteins, Cdo and Boc, localize in cytonemes, and overexpression of either CDO or BOC increases the number of cytonemes detected on mammalian cells ( Hall et al, 2020 ). Further studies are necessary to explore whether the vertebrate Hh co-receptors CDO and BOC also have dual roles in adhesion and signaling along the cytonemes.…”

Competitive coordination of the dual roles of the Hedgehog co-receptor in homophilic adhesion and signal reception

“…Beside the wing imaginal disc epithelia, cytoneme-mediated Hh reception and transport has been described in other Drosophila tissues, such as the abdominal and the female germline stem cell niche (Rojas-Rios et al 2012; Bischoff et al 2013; Gonzalez-Mendez et al 2017). The involvement of cytonemes in Hh signaling has been extended from insect to vertebrates by studies of the limb bud of chick embryo and cultured mouse embryonic fibroblasts (Sanders et al 2013; Hall et al 2020). The vertebrate homologs of the Drosophila Ihog proteins, Cdo and Boc, localize in cytonemes, and overexpression of either CDO or BOC increases the number of cytonemes detected on mammalian cells (Hall et al 2020).…”

“…The involvement of cytonemes in Hh signaling has been extended from insect to vertebrates by studies of the limb bud of chick embryo and cultured mouse embryonic fibroblasts (Sanders et al 2013; Hall et al 2020). The vertebrate homologs of the Drosophila Ihog proteins, Cdo and Boc, localize in cytonemes, and overexpression of either CDO or BOC increases the number of cytonemes detected on mammalian cells (Hall et al 2020). Furthermore, cytonemes have been implicated in the delivery of other paracrine signaling molecules important in development, including Notch, epidermal growth factor, fibroblast growth factor, bone morphogenetic protein, and Wnt (Gonzalez-Mendez et al 2019).…”