PT  - JOURNAL ARTICLE
AU  - Gerard Limerick
AU  - Xia Tang
AU  - Won Suk Lee
AU  - Ahmed Mohamed
AU  - Aseel Al-Aamiri
AU  - William G. Wadsworth
TI  - Stochastic Model of Neuronal Outgrowth Movement: UNC-5 (UNC5) Regulates the Length and Number of Neuronal Processes in <em>Caenorhabditis elegans</em>
AID  - 10.1101/083436
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 083436
4099  - http://biorxiv.org/content/early/2017/03/03/083436.short
4100  - http://biorxiv.org/content/early/2017/03/03/083436.full
AB  - Neurons extend processes that vary in number, length, and direction of outgrowth. Extracellular cues help determine the patterning of outgrowth. In Caenorhabditis elegans, neurons respond to the extracellular UNC-6 (netrin) cue via UNC-40 (DCC) and UNC-5 (UNC5) receptors. We have postulated that UNC-40 undergoes stochastically orientated asymmetric localization (SOAL) within neurons. Extracellular cues govern the probability of UNC-40 localizing and mediating outgrowth at points along the surface of the neuron. For each instance of time there is a probability that UNC-40-mediated outgrowth will occur in a specific direction and so over time the direction of outgrowth fluctuates. Random walk modeling predicts that the degree of fluctuation affects the extent of outgrowth movement. Therefore, different patterns of outgrowth could be caused by regulating UNC-40 SOAL. Here we present evidence that UNC-5 (UNC5) receptor activity regulates UNC-40 SOAL and affects the length and number of processes that neurons develop. We find that loss of UNC-5 function increases the probability of UNC-40-mediated outgrowth in different directions, thereby increasing the degree of fluctuation. Consistent with the model, in unc-5 loss-of-function mutants neurons fail to extend processes to full length or fail to develop multiple processes. We further show genetic interactions that suggest the UNC-5 and SAX-3 (Robo) receptors, and the cytoplasmic proteins, UNC-53 (NAV2), MIG-15 (NIK kinase), and MADD-2 (TRIM), function through specific signaling pathways to regulate UNC-40 SOAL in response to the UNC-6 and EGL-20 (wnt) extracellular cues. We propose genes influence the patterning of neuronal outgrowth by regulating the SOAL process.