The Control of Semaphorin-1a-Mediated Reverse Signaling by Opposing Pebble and RhoGAPp190 Functions in Drosophila

Solomon H. Snyder Department of Neuroscience, Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Neuron (Impact Factor: 15.05). 11/2012; 76(4):721-34. DOI: 10.1016/j.neuron.2012.09.018
Source: PubMed


Transmembrane semaphorins (Semas) serve evolutionarily conserved guidance roles, and some function as both ligands and receptors. However, the molecular mechanisms underlying the transduction of these signals to the cytoskeleton remain largely unknown. We have identified two direct regulators of Rho family small GTPases, pebble (a Rho guanine nucleotide exchange factor [GEF]) and RhoGAPp190 (a GTPase activating protein [GAP]), that show robust interactions with the cytoplasmic domain of the Drosophila Sema-1a protein. Neuronal pebble and RhoGAPp190 are required to control motor axon defasciculation at specific pathway choice points and also for target recognition during Drosophila neuromuscular development. Sema-1a-mediated motor axon defasciculation is promoted by pebble and inhibited by RhoGAPp190. Genetic analyses show that opposing pebble and RhoGAPp190 functions mediate Sema-1a reverse signaling through the regulation of Rho1 activity. Therefore, pebble and RhoGAPp190 transduce transmembrane semaphorin-mediated guidance cue information that regulates the establishment of neuronal connectivity during Drosophila development.

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    • "Drosophila (Cafferty et al., 2006; Godenschwege et al., 2002; Jeong et al., 2012; Komiyama et al., 2007; Yu et al., 2010). Downstream of Sema-1a, RhoGAPp190 and Pebble, a Rho-GEF, function to regulate Rho activity and control motor axon fasciculation and target recognition (Jeong et al., 2012). The ability of such membrane-associated semaphorins to interact with signalling proteins through their cytoplasmic domains suggests that many other semaphorins might be capable of mediating reverse signalling events. "
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    ABSTRACT: Semaphorins are secreted and membrane-associated proteins that regulate many different developmental processes, including neural circuit assembly, bone formation and angiogenesis. Trans and cis interactions between semaphorins and their multimeric receptors trigger intracellular signal transduction networks that regulate cytoskeletal dynamics and influence cell shape, differentiation, motility and survival. Here and in the accompanying poster we provide an overview of the molecular biology of semaphorin signalling within the context of specific cell and developmental processes, highlighting the mechanisms that act to fine-tune, diversify and spatiotemporally control the effects of semaphorins.
    Full-text · Article · Sep 2014 · Development
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    • "Kayam Chak and Alex L. Kolodkin* Development al., 2012; Jeong et al., 2012 "
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    ABSTRACT: The second messengers cAMP and cGMP modulate attraction and repulsion mediated by neuronal guidance cues. We find that the Drosophila receptor guanylyl cyclase Gyc76C genetically interacts with Semaphorin 1a (Sema-1a) and physically associates with the Sema-1a receptor plexin A (PlexA). PlexA regulates Gyc76C catalytic activity in vitro, and each distinct Gyc76C protein domain is crucial for regulating Gyc76C activity in vitro and motor axon guidance in vivo. The cytosolic protein dGIPC interacts with Gyc76C and facilitates Sema-1a-PlexA/Gyc76C-mediated motor axon guidance. These findings provide an in vivo link between semaphorin-mediated repulsive axon guidance and alteration of intracellular neuronal cGMP levels.
    Preview · Article · Nov 2013 · Development
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    ABSTRACT: Background: SEMA6B is a member of the semaphorins axon-guidance family. A growing body of evidence has been accumulated describing the role of semaphorin molecules in cancer development and the involvement of SEMA6B in cancer progression has recently been proposed. Methods: Our analysis, based on real-time PCR, focused on the expression of SEMA6B in a panel of breast cancer tissues, compared to the normal counterpart. Results: In cancer tissues we found a significantly strong down-modulation of this transcript. Moreover we identified and characterized a novel SEMA6B isoform, named SEMA6Ba. This isoform has a novel splice junction, created by the usage of alternative donor and acceptor splice sites internal to the exon 17. By in silico analysis we found that the new transcript 3' UTR lacks some highly-conserved miRNA binding sites, suggesting possible consequences on both spatial and temporal expression of SEMA6Ba. The translated sequence of SEMA6Ba lacks the cytoplasmic tail, crucial for triggering the reverse signaling described for the transmembrane semaphorins. We also demonstrated, by immunofluorescence analysis of endogenous and overexpressed SEMA6Ba, that the protein clearly localized to the endoplasmic reticulum and plasma membrane. In conclusion, SEMA6B gene products are strongly down modulated in breast cancer tissues and a new isoform named SEMA6Ba has been described and characterized. General significance: Our work states a clear relation among breast cancer and SEMA6B expression; moreover we describe for the first time the SEMA6Ba protein and report here the analysis of SEMA6Ba RNA messenger, the protein expression and the cellular localization.
    No preview · Article · May 2013 · Biochimica et Biophysica Acta
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