title: Experimental evidence for UNC-6 (netrin) axon guidance by stochastic fluctuations of intracellular UNC-40 (DCC) outgrowth activity.
abstract: How the direction of axon guidance is determined is not understood. In Caenorhabditis elegans the UNC-40 (DCC) receptor mediates a response to the UNC-6 (netrin) guidance cue that directs HSN axon development. UNC-40 becomes asymmetrically localized within the HSN neuron to the site of axon outgrowth. Here we provide experimental evidence that the direction of guidance can be explained by the stochastic fluctuations of UNC-40 asymmetric outgrowth activity. We find that the UNC-5 (UNC5) receptor and the cytoskeletal binding protein UNC-53 (NAV2) regulate the induction of UNC-40 localization by UNC-6. If UNC-40 localization is induced without UNC-6 by using an unc-53 mutation, the direction of UNC-40 localization undergoes random fluctuations. Random walk models describe the path made by a succession of randomly directed movement. This model was experimentally tested using mutations that affect Wnt/PCP signaling. These mutations inhibit UNC-40 localization in the anterior and posterior directions. As the axon forms in Wnt/PCP mutants, the direction of UNC-40 localization randomly fluctuates; it can localize in either the anterior, posterior, or ventral direction. Consistent with a biased random walk, over time the axon will develop ventrally in response to UNC-6, even though at a discrete time UNC-40 localization and outgrowth can be observed anterior or posterior. Also, axon formation is slower in the mutants than in wild-type animals. This is also consistent with a random walk since this model predicts that the mean square displacement (msd) will increase only linearly with time, whereas the msd increases quadratically with time for straight-line motion.
authors: Department of Pathology, Robert Wood Johnson Medical School, Rutgers University, 675 Hoes Lane West, Piscataway, NJ 08854, USA.
authors: Gauri
authors: G
authors: Kulkarni
authors: Zhennan
authors: Z
authors: Xu
authors: Ahmed M
authors: AM
authors: Mohamed
authors: Haichang
authors: H
authors: Li
authors: Xia
authors: X
authors: Tang
authors: Gerard
authors: G
authors: Limerick
authors: William G
authors: WG
authors: Wadsworth
keywords: Axon guidance; Caenorhabditis elegans; DCC receptor; Netrin; Neurons; Stochastic Process; UNC-6; Wnt signaling