Mechanosignaling

How do neurotrophins, collapsin, and ephrins, serve as guidance cues?

Neurotrophins

Stimulating filopodia formation A secreted guidance cue which stimulates filopodia formation in growth cones. Two examples of secreted neurotrophins, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), mediate retinal ganglion cell axon filopodia [1] and sprouting of axonal filopodia, respectively [2]. Neurotrophins bind Trk receptors and the p75 neurotrophin receptor (p75NTR) to regulate both filopodia assembly and length [3]. Neurotrophins stimulate filopodial assembly by influencing actin-dependent nucleation, polymerization, and motility through PI-3 kinase-dependent signal transduction pathways [4][5].

Collapsin

Inducing filopodia collapse in chick and its mammalian orthologue, semaphorin III (SemaIII) are a few of the most extensively studied proteins that cause repulsion or collapse of growth cones in particular neuronal classes. Members of this group are secreted and transmembrane proteins; they bind to neurophilin receptors to stimulate repulsion (reviewed in [6]). SemaIIIA causes termination of protrusive activity and growth cone collapse [7] through activation of Rac1 [8] and decreased phosphorylation of the ezrin–radixin–moesin (ERM)family of F-actin binding proteins [9]. Phosphorylation of ERM proteins activates the F-actin binding domain and regulates filopodia assembly/protrusion by linking filopodial membranes with F-actin (reviewed in [10]). Inactivation of the phosphoinositide 3-kinase (PI3K) signal pathway by SemaIIIA may also be linked to reduced ERM protein activity and growth cone collapse [9].

Ephrins

Ephrins are contact-dependent guidance cues that induce both attractive and repulsive signals [11]. These signals are transduced via ephrin binding to Eph receptors that belong to the receptor tyrosine kinase family. Binding of membrane-bound ephrins to Eph receptors induces receptor clustering, activation and subsequent signal transduction (forward signaling). The reverse is also true, with Eph receptors able to bind to ephrins, inducing ephrin ligand clustering and subsequently signal transduction (reverse signaling) [12]. Eph-ephrin signaling is therefore bidirectional, with both components able to act as receptor or ligand. Soluble ephrins are also able to bind Eph receptors, but this does not promote signal transduction, unless the ephrins are artificially membrane-bound [13].

Membrane-bound ephrins can be divided into two main classes, determined by sequence homology, which reflect the means by which they attach to the membrane. Ephrin As bind to the membrane via glycosylphosphatidylinositol (GPI) anchors while ephrin Bs traverse the membrane via their transmembrane domain and contain a short cytoplasmic tail [14].

In general ephrin As bind Eph A receptors and ephrin Bs bind Eph B receptors [Gale] and in both instances this facilitates bidirectional signaling, though reverse signaling in ephrin A-Eph A complexes is poorly understood. Both ephrin As and Bs contain a well conserved extracellular domain that binds Eph receptors. Ephrin Bs additionally contain conserved tyrosine phosphorylation sites and a PDZ domain in their cytoplasmic tails that facilitate intracellular signaling (reviewed in [12]).

The primary role of ephrin-Eph receptor signaling is to regulate cellular patterning, e.g. guiding neuronal growth cones to the appropriate target. A significant body of work has elucidated the role of ephrins in neural development (as reviewed in [15]). For example; ephrin Bs are of particular importance in patterning of the hindbrain – a distinctly segmented structure within the brain. Ephrins Bs and their cognate Eph receptors are expressed in complementary domains, such that mixing of neuronal cells is prevented by repulsive cues resulting from the interaction of ephrin Bs and Eph receptors at the interfaces between two adjacent domains [16].

Other processes highly dependent on cell-cell contacts that involve ephrins include the maturation of thymocytes into T-cells of the immune system, the release of insulin from pancreatic beta cells, osteoblast differentiation and segregation of dividing and differentiated cells of the intestinal epithelium. Under pathological conditions, the dysregulation of Eph-ephrin expression has been implicated in cancer and in the development of tumor vasculature (tumour angiogenesis) (reviewed in [17]).

References

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