Academic journal article Genetics

Mechanisms of Ephrin Receptor Protein Kinase-Independent Signaling in Amphid Axon Guidance in Caenorhabditis Elegans

Academic journal article Genetics

Mechanisms of Ephrin Receptor Protein Kinase-Independent Signaling in Amphid Axon Guidance in Caenorhabditis Elegans

Article excerpt

ABSTRACT Eph receptors and their ephrin ligands are key conserved regulators of axon guidance and can function in a variety of signaling modes. Here we analyze the genetic and cellular requirements for Eph signaling in a Caenorhabditis elegans axon guidance choice point, the ventral guidance of axons in the amphid commissure. The C. elegans Eph receptor EFN-1 has both kinase-dependent and kinase-independent roles in amphid ventral guidance. Of the four C. elegans ephrins, we find that only EFN-1 has a major role in amphid axon ventral guidance, and signals in both a receptor kinase-dependent and kinase-independent manner. Analysis of EFN-1 and EFN-1 expression and tissue-specific requirements is consistent with a model in which VAB-1 acts in amphid neurons, interacting with EFN-1 expressed on surrounding cells. Unexpectedly, left-hand neurons are more strongly affected than right-hand neurons by loss of Eph signaling, indicating a previously undetected left-right asymmetry in the requirement for Eph signaling. By screening candidate genes involved in Eph signaling, we find that the Eph kinase-independent pathway involves the ABL-1 nonreceptor tyrosine kinase and possibly the phosphatidylinositol 3-kinase pathway. Overexpression of ABL-1 is sufficient to rescue EFN-1 ventral guidance defects cell autonomously. Our results reveal new aspects of Eph signaling in a single axon guidance decision in vivo.

EPHRINS and their cell surface receptors, the Eph receptor tyrosine kinases (EphR), play critical roles in many axon guidance processes, including midline guidance and growth cone collapse (Drescher et al. 1995; Cowan et al. 2000). In contrast to long-range guidance cues, Eph signaling involves short-range interactions between a transmembrane receptor and transmembrane (ephrin-B) or GPI-linked (ephrin-A) li- gands. Eph signaling is complex and multifunctional, capa- ble of mediating both repulsion and attraction depending on ephrin concentration even in the same neurons (Hansen et al. 2004). Many of the signaling pathways downstream of Eph receptors and ephrins regulate cell movement or cell adhesion (Kullander and Klein 2002; Pasquale 2005).

Because Eph receptors and ephrins are cell surface molecules, they can operate in a variety of signaling modes (Kullander and Klein 2002; Egea and Klein 2007; Pasquale 2008). Eph receptors can generate kinase-dependent "for- ward" signals, in which ligand binding triggers receptor dimerization, activating the intrinsic kinase activity of the receptor, and initiating responses in the receptor-expressing cell. Kinase-dependent forward Eph signaling contributes to many processes including retinotopic mapping (Hindges et al. 2002), axonal midline avoidance after crossing (Yokoyama et aL 2001), neural crest cell migration (Smith et aL 1997), and migration of neural progenitors (Catchpole and Henkemeyer 2011). This regulation of diverse developmental processes occurs in part via kinase-dependent interactions with down- stream effectors including Src-family kinases (Zisch et al. 1998; Knoll and Drescher 2004), Rho GTPases (Wahl et al. 2000; Noren and Pasquale 2004), and RhoGEFs (Shamah et al. 2001; Sahin et al. 2005).

In addition to kinase-dependent signaling, some Eph receptors initiate kinase-independent forward signals. In HEK293 cells, EphA8 signals promote integrin activity via the phosphatidylinositol 3-kinase (PI3K) pathway; the juxtamembrane domain of EphA8 directly interacts with the PI3K catalytic subunit pllO-y, independent of EphA8 kinase activity (Gu and Park 2001, 2003). EphA8 can also interact with the Anks (ankyrin and sterile alpha motif) proteins AIDA and Odin in a kinase-independent manner (Shin et al. 2007). However, the significance of kinase- independent forward signaling in vivo has not been exten- sively analyzed. Reverse signaling via ephrin ligands can also contribute to kinase-independent functions. Although both ephrin-B and ephrin-A ligands are capable of reverse signaling (Bruckner et al. …

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