Differential ligand regulation of PlexB signaling in motor neuron axon guidance in Drosophila

Abstract

Plexins (Plexs) are a large family of phylogenetically conserved guidance receptors that bind specifically to semaphorins (Semas), another large family of guidance molecules. In the Drosophila embryonic central nervous system (CNS), the secreted semaphorins Sema-2a and Sema-2b both act as ligands for PlexB, but mediate mutually independent and opposite functions (repulsive and attractive guidance, respectively). PlexB is also known to regulate motor axon guidance in the embryonic peripheral nervous system (PNS). However, it is unclear whether the mechanisms of ligand regulation of PlexB seen in the CNS are similar or the same as those that exist in PNS motor axon guidance. Here, we find that two distinct modes of ligand regulation underlie differential roles of PlexB in PNS motor axon pathfinding during embryonic development. Epistasis analyses in the intersegmental nerve b (ISNb) pathway suggest that PlexB serves as a receptor for both Sema-2a and Sema-2b and integrates their mutually dependent but opposite guidance functions. Furthermore, we present evidence that PlexB mediates not only Sema-2a/2b-dependent guidance functions, but also Sema-2a/2b-independent target recognition in establishing the segmental nerve a (SNa) motor axon pathway. These results demonstrate that a single guidance receptor can elicit diverse effects on the establishment of neuronal connectivity via regulation of its ligands themselves.

Plexin-Semaphorin Signaling Modifies Neuromuscular Defects in a Drosophila Model of Peripheral Neuropathy

“…In both invertebrates and vertebrates, plexin signaling drives the attractive and repulsive signals required for high-fidelity nerve-nerve, nerve-muscle and nerve-glia interactions (Winberg et al, 1998 ; Hu et al, 2001 ; Ayoob et al, 2006 ; Berke and Keshishian, 2011 ; Roh et al, 2016 ; Syed et al, 2016 ). Although CMT2D is thought to be primarily degenerative in nature, neurodevelopment and maturation defects are observed in invertebrate (Grice et al, 2015b ) and vertebrate (Sleigh et al, 2014b , 2017a ) models, with motor neuron migration (He et al, 2015 ) and sensory neuron branching defects seen in mutant mouse embryos (Sleigh et al, 2017a ).…”

“…In this study, we use the larval NMJ to examine the interaction between the plexin-semaphorin components and mutant GlyRS toxicity. However, unravelling the complete contribution of plexin-semaphorin signaling to CMT2D, in both the peripheral and central nervous systems, is made difficult by the complexity of the temporally and spatially diverse functions mediated through both plexin types (Neufeld et al, 2011 ; Roh et al, 2016 ). For example, Drosophila PlexA has been shown to drive repulsive axon guidance cues in the embryo, whilst PlexB can initiate either repulsive or attractive cell-cell interactions depending on the cellular environment (Winberg et al, 1998 ; Berke and Keshishian, 2011 ; Wu et al, 2011 ; Jeong et al, 2012 ).…”

“…For example, Drosophila PlexA has been shown to drive repulsive axon guidance cues in the embryo, whilst PlexB can initiate either repulsive or attractive cell-cell interactions depending on the cellular environment (Winberg et al, 1998 ; Berke and Keshishian, 2011 ; Wu et al, 2011 ; Jeong et al, 2012 ). In addition, the repulsive and attractive actions are mediated though different ligands and interact with different downstream effectors (Winberg et al, 1998 ; Hu et al, 2001 ; Ayoob et al, 2006 ; Bates and Whitington, 2007 ; Berke and Keshishian, 2011 ; Cho et al, 2012 ; Roh et al, 2016 ). Plexin A binds strongly to the Sema1 class of semaphorins, while Plexin B binds to the Sema2 class (Winberg et al, 1998 ; Ayoob et al, 2006 ; Bates and Whitington, 2007 ).…”

Varicose and cheerio collaborate with pebble to mediate semaphorin-1a reverse signaling in Drosophila

“…However, neither the vari 327 nor cher Q1042X alleles genetically interact with the Sema-2a B65 null allele ( Fig. 5), even though Sema-2a plays an important role in both CNS and PNS axon guidance during embryonic neural development (36,37). Furthermore, when vari 327 and cher Q1042X alleles were combined in transheterozygous configuration, we observed a synergistic increase in total ISNb guidance defects, demonstrating genetic interactions between vari 327 and cher Q1042X (Fig.…”

Characterization of plexinA and two distinct semaphorin1a transcripts in the developing and adult cricket Gryllus bimaculatus

“…Semas can act as repellents or attractants during development in both vertebrates (Polleux, Morrow, & Ghosh, 2000) and invertebrates (Wu et al, 2011). Semas act to guide axons to their target regions in vertebrates (Falk et al, 2005;Renzi, Wexler, & Raper, 2000) and insects (Isbister, Tsai, Wong, Kolodkin, & O'Connor, 1999;Roh, Yang, & Jeong, 2016), and they also help guide and shape maturing dendrites in rodents (Fenstermaker, Chen, Ghosh, & Yuste, 2004;Morita et al, 2006;Tran et al, 2009) and in flies (Hernandez-Fleming, Rohrbach, & Bashaw, 2017;Jan & Jan, 2003;Kim & Chiba, 2004;Syed, Gowda, Reddy, Reichert, & VijayRaghavan, 2016). In addition, Sema signaling is important for synapse formation during development of vertebrate and invertebrate nervous systems (Murphey, 2003;Nakamura et al, 2009).…”