Roles for netrin signaling outside of axon guidance: A view from the worm

Abstract

The Netrin family of extracellular ligands and their receptors were the first identified signaling pathway regulating axon guidance. Subsequent work across model systems has begun to reveal the interactions that take place downstream of Netrin reception to facilitate growth cone migration. Though intensely studied, many aspects of this signaling system remain unclear. Even less understood are the growing number of contexts in which Netrin signaling influences cells beyond axon guidance and even outside the nervous system. Genetic and cell-biological studies in C. elegans have played an instrumental role in identifying critical functions for Netrin ligands in setting up specialized and potentially adhesive membrane-associated domains within a broad range of cell types. Here we review recent literature implicating Netrin or its receptors in morphogenetic processes outside of growth cone regulation with a special focus on studies in C. elegans that suggest cell biological mechanisms for Netrin signaling.

Cell Invasion In Vivo via Rapid Exocytosis of a Transient Lysosome-Derived Membrane Domain

“…Supporting this possibility, UNC-40 contains the intracellular P3 domain that has been implicated in regulating interactions with vertebrate SNAP25 during exocytosis (Winkle et al, 2014; Ziel and Sherwood, 2010). Uterine-specific RNAi knockdown of snap-29 disrupted AC invasion to the same extent as whole body treatment (Table S1), suggesting that SNAP-29 functions in the AC.…”

“…The vertebrate UNC-40 receptor DCC interacts with the vertebrate homolog of SNAP-29 (the t-SNARE SNAP-25) to mediate exocytosis of membrane for axon outgrowth and branching (Winkle et al, 2014). Biochemical evidence suggests that this is directed in part through the intracellular P3 domain of DCC, a domain shared with UNC-40 (Winkle et al, 2014; Ziel and Sherwood, 2010). Notably, DCC/SNAP-25 exocytosis is partially dependent on VAMP-7, a lysosomal V-SNARE (Winkle et al, 2014), suggesting a similar lysosomal membrane source is also used in neurons.…”

Regulating distal tip cell migration in space and time

“…UNC-6/netrin signaling is the key regulator of this first turn (14). UNC-6/netrin is a laminin-like secreted protein that provides directional information to many types of migrating cells including neurons and the DTCs (15).…”

Cell invasion through basement membrane

“…For example, localization and activity of UNC-40 in muscle arm extension does not depend upon UNC-6 (netrin) 32 . Further, elongation of the AVM axon along the anterior-posterior axis and the posterior migration of the Q L neuroblast require UNC-40 (DCC) signaling without UNC-6 33 . It’s unknown in these instances how UNC-40 signals or is localized without UNC-6.…”