Emerging evidence for cell-autonomous axon guidance.

ABSTRACT

Current models of axon guidance within the central nervous system (CNS) involve the presentation of environmental cues to navigating growth cones. The surrounding and target tissues present a variety of ligands that either restrict or promote growth, thus providing pathfinding instructions to developing axons. Recent findings show that RGMb, a GPI anchored extracellular protein present on retinal ganglion cells, down-regulates Wnt3a signaling by lowering LRP5 levels at the membrane surface. When RGMb is phosphorylated by the extracellular tyrosine kinase VLK, phosphorylated RGMb (p-RGMb) is internalized and carries LRP5 towards intracellular compartments. In the eye, a dorsal-high ventral-low gradient of VLK generates a dorsal-low ventral-high gradient of LRP5 that modulates Wnt3a signaling. These molecules, which are all expressed by individual RGCs, generate Wnt-signal gradients along the dorso-ventral axis of the retina, resulting in differential axon growth which in turn regulates proper retino-tectal/collicular map formation. This pathway represents a regulatory mechanism whereby extracellular phosphorylation generates what may be the first example of a unique self-guiding mechanism that affects neuronal-target connections independent of paracrine signals from the surrounding target tissue.