Netrin 1 and Dcc signalling are required for confinement of central axons within the central nervous system (original) (raw)
Related papers
Netrin-1 Acts as a Repulsive Guidance Cue for Sensory Axonal Projections toward the Spinal Cord
Journal of Neuroscience, 2008
During early development, the ventral spinal cord expresses chemorepulsive signals that act on dorsal root ganglion (DRG) axons to help orient them toward the dorsolateral part of the spinal cord. However, the molecular nature of this chemorepulsion is mostly unknown. We report here that netrin-1 acts as an early ventral spinal cord-derived chemorepellent for DRG axons. In the developing mouse spinal cord, netrin-1 is expressed in the floor plate of the spinal cord, and the netrin receptor Unc5c is expressed in DRG neurons. We show that human embryonic kidney cell aggregates secreting netrin-1 repel DRG axons and that netrin-1-deficient ventral spinal cord explants lose their repulsive influence on DRG axons. In embryonic day 10 netrin-1 mutant mice, we find that DRG axons exhibit transient misorientation. Furthermore, by means of gain-of-function analyses, we show that ectopic netrin-1 in the dorsal and intermediate spinal cord prevents DRG axons from being directed toward the dorsal spinal cord. Together, these findings suggest that netrin-1 contributes to the formation of the initial trajectories of developing DRG axons as a repulsive guidance cue.
Cerebral Cortex, 2014
The left and right sides of the nervous system communicate via commissural axons that cross the midline during development using evolutionarily conserved molecules. These guidance cues have been particularly well studied in the mammalian spinal cord, but it remains unclear whether these guidance mechanisms for commissural axons are similar in the developing forebrain, in particular for the corpus callosum, the largest and most important commissure for cortical function. Here, we show that Netrin1 initially attracts callosal pioneering axons derived from the cingulate cortex, but surprisingly is not attractive for the neocortical callosal axons that make up the bulk of the projection. Instead, we show that Netrindeleted in colorectal cancer signaling acts in a fundamentally different manner, to prevent the Slit2-mediated repulsion of precrossing axons thereby allowing them to approach and cross the midline. These results provide the first evidence for how callosal axons integrate multiple guidance cues to navigate the midline.
UNC-6/Netrin induces neuronal asymmetry and defines the site of axon formation
Nature Neuroscience, 2006
6/Netrin and its receptor UNC-40/DCC are conserved regulators of growth cone guidance. By directly observing developing neurons in vivo, we show that UNC-6 and UNC-40 also function during axon formation to initiate, maintain and orient asymmetric neuronal growth. The immature HSN neuron of Caenorhabditis elegans breaks spherical symmetry to extend a leading edge toward ventral UNC-6. In unc-6 and unc-40 mutants, leading edge formation fails, the cell remains symmetrical until late in development and the axon that eventually forms is misguided. Thus netrin has two activities: one that breaks neuronal symmetry and one that guides the future axon. As the axon forms, UNC-6, UNC-40 and the lipid modulators AGE-1/phosphoinositide 3-kinase (PI3K) and DAF-18/PTEN drive the actin-regulatory pleckstrin homology (PH) domain protein MIG-10/lamellipodin ventrally in HSN to promote asymmetric growth. The coupling of a directional netrin cue to sustained asymmetric growth via PI3K signaling is reminiscent of polarization in chemotaxing cells.
A new model for netrin1 in commissural axon guidance
Journal of Neuroscience Research, 2017
Now-classic experiments characterized netrin1 as a major player in commissural axon guidance in the spinal cord. The data suggest a chemotactic model in which netrin1 expression in the floor plate forms a concentration gradient that attracts commissural axons. New research published independently in Neuron and in Nature tests this model by deleting netrin1 specifically in the floor plate. Surprisingly, these conditional mutant mice have no overt commissure defects. The authors report that netrin1 decorates the pial surface of the spinal cord and hindbrain, likely deposited by radial processes of progenitor cells in the ventricular zone. They find that deletion of the cue exclusively in the ventricular zone causes commissural axons to take aberrant trajectories, suggesting a short range, haptotactic guidance mechanism as opposed to chemotaxis. This minireview aims to summarize the classic and the new findings and offer some interpretations of the data.
Development, 2006
Dorsal root ganglion (DRG) neurons extend axons to specific targets in the gray matter of the spinal cord. During development, DRG axons grow into the dorsolateral margin of the spinal cord and projection into the dorsal mantle layer occurs after a `waiting period' of a few days. Netrin 1 is a long-range diffusible factor expressed in the ventral midline of the developing neural tube, and has chemoattractive and chemorepulsive effects on growing axons. Netrin 1 is also expressed in the dorsal spinal cord. However, the roles of dorsally derived netrin 1 remain totally unknown. Here, we show that dorsal netrin 1 controls the correct guidance of primary sensory axons. During the waiting period, netrin 1 is transiently expressed or upregulated in the dorsal spinal cord, and the absence of netrin 1 results in the aberrant projection of sensory axons, including both cutaneous and proprioceptive afferents, into the dorsal mantle layer. Netrin 1 derived from the dorsal spinal cord, but ...
Dscam guides embryonic axons by Netrin-dependent and -independent functions
Development, 2008
Developing axons are attracted to the CNS midline by Netrin proteins and other as yet unidentified signals. Netrin signals are transduced in part by Frazzled (Fra)/DCC receptors. Genetic analysis in Drosophila indicates that additional unidentified receptors are needed to mediate the attractive response to Netrin. Analysis of Bolwig's Nerve reveals that Netrin mutants have a similar phenotype to Down Syndrome Cell Adhesion Molecule (Dscam) mutants. Netrin and Dscam mutants display dose sensitive interactions suggesting that Dscam could act as a Netrin receptor. We show using cell overlay assays that Netrin binds to fly and vertebrate Dscam, and that Dscam binds Netrin with the same affinity as DCC. At the CNS midline, we find that Dscam and its paralog Dscam3 act redundantly to promote midline crossing. Simultaneous genetic knockout of the two Dscams and the Netrin receptor fra produces a midline crossing defect that is stronger than the removal of Netrins, suggesting that Dscams also function in a pathway parallel to Netrins. Additionally, over-expression of Dscam in axons that do not normally cross the midline is able to induce ectopic midline crossing, consistent with an attractive receptor function. Our results support the model that Dscams function as attractive receptors for Netrin and also act in parallel to Frazzled/DCC. Furthermore, the results suggest that Dscams have the ability to respond to multiple ligands and act as receptors for an unidentified midline attractive cue. These functions in axon guidance have implications for the pathogenesis of Down Syndrome.