Abstract
Olfm1, a secreted highly conserved glycoprotein, is detected in peripheral and central nervous tissues and participates in neural progenitor maintenance, cell death in brain, and optic nerve arborization. In this study, we identified Olfm1 as a molecule promoting axon growth through interaction with the Nogo A receptor (NgR1) complex. Olfm1 is coexpressed with NgR1 in dorsal root ganglia and retinal ganglion cells in embryonic and postnatal mice. Olfm1 specifically binds to NgR1, as judged by alkaline phosphatase assay and coimmunoprecipitation. The addition of Olfm1 inhibited the growth cone collapse of dorsal root ganglia neurons induced by myelin-associated inhibitors, indicating that Olfm1 attenuates the NgR1 receptor functions. Olfm1 caused the inhibition of NgR1 signaling by interfering with interaction between NgR1 and its coreceptors p75NTR or LINGO-1. In zebrafish, inhibition of optic nerve extension by olfm1 morpholino oligonucleotides was partially rescued by dominant negative ngr1 or lingo-1. These data introduce Olfm1 as a novel NgR1 ligand that may modulate the functions of the NgR1 complex in axonal growth.
Highlights
Olfactomedin 1 (Olfm1) is a highly conserved secreted glycoprotein with an unknown mechanism of action
To test possible binding of Olfm1 to selected proteins, we used Conditioned medium (CM) of COS7 cells transiently transfected with a construct encoding the Olfm1 alkaline phosphatase fusion protein (Olfm1-AP)
COS7 cells were incubated with Olfm1-AP CM, and the activities of AP bound to cell membrane were visualized by staining using nitro-blue tetrazolium and 5bromo-4-chloro-3Ј-indolyphosphate as substrates
Summary
Olfactomedin 1 (Olfm1) is a highly conserved secreted glycoprotein with an unknown mechanism of action. We identified Olfm as a molecule promoting axon growth through interaction with the Nogo A receptor (NgR1) complex. In the adult mammalian CNS, axonal growth is largely restricted by barriers provided by glial cells [13] These barriers are formed by membrane proteins, including myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), Nogo A [14], and chondroitin sulfate proteoglycans [15] on the glial surface. Each of these membrane proteins interacts with the Nogo A receptor complex, which consists of Nogo A receptor 1 (NgR1) and putative coreceptors (p75NTR, LINGO-1, and TROY) [16] These receptors are expressed at the growth cones where ligand binding induces reorganization of the cytoskeleton, resulting in growth cone repulsion or collapse. Olfm and ngr interact to regulate the optic nerve extension
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