EFN-4/Ephrin functions in LAD-2/L1CAM-mediated axon guidance in Caenorhabditis elegans

Abstract

During development of the nervous system, growing axons rely on guidance molecules to direct axon pathfinding. A well-characterized family of guidance molecules are the membrane-associated ephrins, which together with their cognate Eph receptors, direct axon navigation in a contact-mediated fashion. In C. elegans, the ephrin-Eph signaling system is conserved and is best characterized for their roles in neuroblast migration during early embryogenesis. This study demonstrates a role for the C. elegans ephrin EFN-4 in axon guidance. We provide both genetic and biochemical evidence that is consistent with the C. elegans divergent L1 cell adhesion molecule LAD-2 acting as a non-canonical ephrin receptor to EFN-4 to promote axon guidance. We also show that EFN-4 probably functions as a diffusible factor because EFN-4 engineered to be soluble can promote LAD-2-mediated axon guidance. This study thus reveals a potential additional mechanism for ephrins in regulating axon guidance and expands the repertoire of receptors by which ephrins can signal.

The Genetics of Axon Guidance and Axon Regeneration in Caenorhabditis elegans

“…EFN-1 functions to guide amphid axons ventrally through the amphid commissure Grossman et al 2013); amphid axon ventral guidance also involves partly redundant SAX-3 and netrin signals. EFN-4 also signals via noncanonical mechanisms that do not involve VAB-1 (Chin-Sang et al 2002), and interacts with the L1CAM LAD-2 to provide a cue for the dorsal migration of the SDQ axons (Dong et al 2016). EFN-4 is also required for AIY and D-type motorneuron axon outgrowth, as these axons stop prematurely in efn-4 mutants .…”

The regulatory landscape of neurite development in Caenorhabditis elegans

“…Some members of the Semaphorin family and ECM components are released from cells to guide axons. For example, MAB-20/Sema2 is a secreted semaphorin that interacts with PLX-2/Plexin and LAD-2/L1CAM to guide axons of the DA, DB and SDQL neurons ( Roy et al, 2000 ; Wang et al, 2008 ; Dong et al, 2016 ). While ECM components, such as the metalloprotease MADD-4, are secreted from dorsal and VNC and cooperate with UNC-6/Netrin and SLT-1/Slit to control both muscle arm extension and AVM axon guidance following interaction with the UNC-40/DCC receptor ( Seetharaman et al, 2011 ).…”

“…Correct neurite development is therefore critical for efficient signal transduction between neurons within a neuronal circuit. During development, neurites are guided to their targets by attractive and repulsive cues from surrounding cells/tissues and the extracellular matrix (ECM) ( Adler et al, 2006 ; Wang et al, 2008 ; Dong et al, 2016 ; Miller and Suter, 2018 ). Many conserved ligands and receptors involved in neurite guidance have been identified over the last three decades ( Tables 1 , 2 ).…”