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SAX-3 (Robo) and UNC-40 (DCC) Regulate a Directional Bias for Axon Guidance in Response to Multiple Extracellular Cues

by
Xia Tang
Xia Tang
B.S., Tsinghua University - 2010

Thesis Advisor: William Wadsworth, Ph.D.
Graduate Program in Cell and Developmental Biology

RWJMS, Research Tower
Room V-14
Piscataway

Friday, February 27, 2015
10:00 a.m.


Abstract

A functional nervous system requires precise and integral neuronal connections to be made. Axon guidance process makes sure that axon reaches its destination accurately. Guidance information is provided by extracellular guidance cues and “read” by growth cones, a highly motile structure at the growing tips of axons. Yet, the mechanism of how growth cone integrates simultaneously multiple guidance cues to produce a precise direction response is not known.
We study the axon guidance of C.elegans HSN and AVM neurons. They are guided by multiple extracellular cues, including UNC-6 (Netrin), EGL-20 (Wnt), UNC-52 (Perlecan), and SLT-1 (Slit). Previously, it is believed that axons are guided towards their targets via attraction or repulsion forces in a “deterministic” manner. These signals work in parallel to ensure precise wiring. However, we propose that guidance cues cause axon outgrowth activity to move stochastically, which can be formulated as a random walk. We have evidence that the UNC-40 receptor mediates multiple signals to provide one such outgrowth activity: a polarization signal causes random clustering of UNC-40 along the cell surface; an orientation signal biases the clustered UNC-40 towards a particular direction. Guidance cues determine the probability of UNC-40 fluctuation in each direction, which over time creates a directional bias for guidance. Here we provide evidence that SAX-3 is required to induce the polarization of UNC-40 mediated axon outgrowth activity. We describe how the UNC-40 (DCC) and SAX-3 (Robo) receptors and the UNC-6, EGL-20, UNC-52, and SLT-1 extracellular cues affect the directional bias of the axon outgrowth activity for the HSN and AVM neurons respectively. We find that UNC-40 and SAX-3 are required to maintain and transduce the directional bias created by these cues. UNC-6 and EGL-20 affect the directional bias for both neurons, while UNC-52 and SLT-1 only affect the directional bias for HSN and AVM, respectively. Together these signaling produces a combinatorial regulation machinery for axon movement.


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