Abstract
Morphogens function in concentration-dependent manners to instruct cell fate during tissue patterning. The cytoneme morphogen transport model posits that specialized filopodia extend between morphogen-sending and responding cells to ensure that appropriate signaling thresholds are achieved. How morphogens are transported along and deployed from cytonemes, how quickly a cytoneme-delivered, receptor-dependent signal is initiated, and whether these processes are conserved across phyla are not known. Herein, we reveal that the actin motor Myosin 10 promotes vesicular transport of Sonic Hedgehog (SHH) morphogen in mouse cell cytonemes, and that SHH morphogen gradient organization is altered in neural tubes of Myo10-/- mice. We demonstrate that cytoneme-mediated deposition of SHH onto receiving cells induces a rapid, receptor-dependent signal response that occurs within seconds of ligand delivery. This activity is dependent upon a novel Dispatched (DISP)-BOC/CDON co-receptor complex that functions in ligand-producing cells to promote cytoneme occurrence and facilitate ligand delivery for signal activation.
Highlights
The Hedgehog (HH) pathway is an evolutionarily conserved signaling relay that contributes to embryonic development through influencing cell fate, cell proliferation, cell and tissue polarity, stem cell maintenance, and tissue homeostasis
HH family morphogens, which include HH in flies and Sonic (SHH), Desert (DHH) and Indian (IHH) Hedgehogs in vertebrates, function in concentration-dependent manners to instruct tissue morphogenesis through Patched (PTCH) receptors and Cell Adhesion Molecule-Related/Down-Regulated by Oncogenes (CDON), Brother of CDON (BOC) or Growth Arrest-Specific 1 (GAS1) coreceptors (Allen et al, 2007; Marigo et al, 1996; Okada et al, 2006; Yao et al, 2006)
We find that disruption of Myosin 10 (MYO10) in vivo leads to neural tube patterning defects consistent with attenuated Sonic Hedgehog (SHH) morphogen gradient function, confirming that cell-based interrogation of cytonemes can predict in vivo relevance
Summary
The Hedgehog (HH) pathway is an evolutionarily conserved signaling relay that contributes to embryonic development through influencing cell fate, cell proliferation, cell and tissue polarity, stem cell maintenance, and tissue homeostasis (reviewed in Briscoe and Therond, 2013). HH family morphogens, which include HH in flies and Sonic (SHH), Desert (DHH) and Indian (IHH) Hedgehogs in vertebrates, function in concentration-dependent manners to instruct tissue morphogenesis through Patched (PTCH) receptors and Cell Adhesion Molecule-Related/Down-Regulated by Oncogenes (CDON), Brother of CDON (BOC) or Growth Arrest-Specific 1 (GAS1) coreceptors (Allen et al, 2007; Marigo et al, 1996; Okada et al, 2006; Yao et al, 2006). Binding of SHH to PTCH receptor complexes allows for activation of the G-protein-coupled receptor Smoothened (SMO), which can signal through both G-protein-dependent and independent effector routes to induce downstream responses (reviewed in Arensdorf et al, 2016). G-protein-dependent noncanonical SMO signals induce transcription-independent responses including cytoskeletal
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