Myosin X regulates netrin receptors and functions in axonal path-finding

Abstract

Netrins regulate axon path-finding during development, but the underlying mechanisms are not well understood. Here, we provide evidence for the involvement of the unconventional myosin X (Myo X) in netrin-1 function. We find that Myo X interacts with the netrin receptor deleted in colorectal cancer (DCC) and neogenin, a DCC-related protein. Expression of Myo X redistributes DCC to the cell periphery or to the tips of neurites, whereas its silencing prevents DCC distribution in neurites. Moreover, expression of DCC, but not neogenin, stimulates Myo X-mediated formation and elongation of filopodia, suggesting that Myo X function may be differentially regulated by DCC and neogenin. The involvement of Myo X in netrin-1 function was further supported by the effects of inhibiting Myo X function in neurons. Cortical explants derived from mouse embryos expressing a motor-less Myo X exhibit reduced neurite outgrowth in response to netrin-1 and chick commissural neurons expressing the motor-less Myo X, or in which Myo X is silenced using microRNA (miRNA), show impaired axon projection in vivo. Taken together, these results identify a novel role for Myo X in regulating netrin-1 function.

Neogenin Regulates Skeletal Myofiber Size and Focal Adhesion Kinase and Extracellular Signal-regulated Kinase Activities In Vivo and In Vitro

“…Several signaling pathways are activated by netrin signaling through DCC/UNC40 family members, although neogenin is understudied compared with its mammalian paralogue DCC (Forcet et al, 2002;Campbell and Holt, 2003;Li et al, , 2008Liu et al, 2004;Ren et al, 2004;Xie et al, 2005;Zhu et al, 2007). Both FAK and ERK are activated by, and required for, netrin-1/DCC signaling in axon guidance (Forcet et al, 2002;Campbell and Holt, 2003;Li et al, 2004;Liu et al, 2004;Ren et al, 2004).…”

“…Netrin-1 treatment of neurons also leads to DCC-dependent activation of ERK mitogen-activated protein kinase (MAPK) and inhibition of ERK signaling blocks neurite outgrowth and growth cone turning in response to a netrin gradient in vitro (Forcet et al, 2002;Campbell and Holt, 2003). Additional signaling pathways are also activated by netrin-1 signaling via DCC and neogenin (Xie et al, 2005;Zhu et al, 2007;Li et al, 2008).…”

“…Netrin-1 treatment of neurons also leads to DCC-dependent activation of ERK mitogen-activated protein kinase (MAPK) and inhibition of ERK signaling blocks neurite outgrowth and growth cone turning in response to a netrin gradient in vitro (Forcet et al, 2002;Campbell and Holt, 2003). Additional signaling pathways are also activated by netrin-1 signaling via DCC and neogenin (Xie et al, 2005;Zhu et al, 2007;Li et al, 2008).Although neogenin and DCC are similar in their signaling responses to netrin-1 (although not identical, see Xie et al, 2006;Ren et al, 2008), neogenin plays a broader role in development than DCC. First, neogenin, but not DCC, binds to members of a second family of ligands, the GPI-anchored repulsive guidance molecules (RGMa, RGMb, and RGMc) (Rajagopalan et al, 2004;Zhang et al, 2005).…”

Neogenin regulates neuronal survival through DAP kinase

“…The ICD of neogenin has P1, P2, and P3 domains that are functionally important. 18 Various deletion constructs of neogenin ICD were used as shown in Figure 3b. The results demonstrate that both P2 and P3 domains were necessary for the interaction with the death domain of DAPK (Figure 3b).…”

Listen to your gut: Using adhesion to shape the surface of functionally diverse epithelia

“…14 Other actin-based protrusions that accumulate specific factors at their tips have invoked myosin motors to drive transport to and enrichment at the barbed-ends of supporting actin bundles (e.g., myosin-10 in filopodia). [16][17][18][19][20][21] A myosin motor might play a similar role in microvilli as the cytoplasmic domains of CDHR2 and CDHR5 interact with the tandem MyTH4/FERM (MF) domain motor, myosin-7b (MYO7B). 14 CDHR2, CDHR5, and MYO7B also interact with the PDZ domain scaffolding protein, USH1C, which likely enhances the lifetime of interactions between the motor and its cargo (i.e., the protocadherins).…”