Samantha Butler, PhD
Associate Professor
Department of Neurobiology
University of California, Los Angeles
October 23, 2018
Rethinking the Role of Netrin1 in Axon Guidance: Chemotaxis vs. Haptotaxis?
How do neurons find their way to connect with one another? How do axons, the “strings” that send signals from one neuron to another, connect with the correct partners to form circuits? Previous thinking focused on chemical signaling to orient axons to the right direction. Dr. Butler and her lab have explored the signaling used to guide axonal growth in the developing spinal cord. It was previously assumed that a chemical signal, netrin1, was produced by cells to promote axon growth in a particular direction. Dr. Butler has determined that neptin1 may actually be produced by neural stem cells (or “progenitor” cells), and may act as a surface on which the axon can grow, rather than a chemical signal.
Neural circuits are established during development when neurons send out processes, called axons, into the embryo. Axons navigate to their destinations using molecular guidance cues in the embryonic environment to direct the path of axon extension. Previous research in the field had suggested that axons are guided by chemotropic guidance cues: long-distance diffusible signals that function like a harbor beacon orienting a ship from afar. The textbook example of this mechanism was the ability of netrin1 to guide commissural axons in the developing spinal cord. However, recent studies from my laboratory have rather shown that netrin1 promotes axon extension not by long-range chemotaxis, but rather by haptotaxis, the directed growth of cells along an adhesive surface, akin to the holds used by climbers to pioneer a path to the top of a mountain.
These studies have led to a reevaluation of the mechanisms by which netrin1 establishes neural circuitry and how netrin1 may be best deployed to regenerate damaged circuitry. Netrin1 was hypothesized to act as a chemoattractant for dorsal spinal commissural axons. In this model, netrin1 was secreted from a cluster of cells at the ventral midline, called the floor plate, to promote the growth of commissural axons specifically towards the ventral midline.
Our studies have recently shown that this model is wrong. Rather, the key source of netrin1 that guides commissural axons in the spinal cord appears to be supplied by neural progenitor cells (NPCs), neural specific stem cells that reside in a compartment of the spinal cord called the ventricular zone.
In our model, the NPCs make netrin1 protein, and then transfer it along their specialized radial processes to the outer edge of the spinal cord, where netrin1 is deposited as a haptotactic growth substrate. Commissural neurons orient their growth of their axons to extend immediately adjacent to this netrin1+ substrate. Removing even a small part of this netrin1+ substrate (i.e. one of the “holds” in the analogy above) results in a profound, local perturbation of the pattern of axon growth. In contrast, specifically removing netrin1 from the floor plate (i.e. the “harbor beacon”) has no effect on axon growth. These studies reveal a previously unappreciated property of NPCs: they can use their cellular geometry to orient and promote the axonal trajectories of their own neural progeny.