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Regulation of chemotropic guidance of nerve growth cones by microRNA.

ABSTRACT: BACKGROUND:The small non-coding microRNAs play an important role in development by regulating protein translation, but their involvement in axon guidance is unknown. Here, we investigated the role of microRNA-134 (miR-134) in chemotropic guidance of nerve growth cones. RESULTS:We found that miR-134 is highly expressed in the neural tube of Xenopus embryos. Fluorescent in situ hybridization also showed that miR-134 is enriched in the growth cones of Xenopus spinal neurons in culture. Importantly, overexpression of miR-134 mimics or antisense inhibitors blocked protein synthesis (PS)-dependent attractive responses of Xenopus growth cones to a gradient of brain-derived neurotrophic factor (BDNF). However, miR-134 mimics or inhibitors had no effect on PS-independent bidirectional responses of Xenopus growth cones to bone morphogenic protein 7 (BMP7). Our data further showed that Xenopus LIM kinase 1 (Xlimk1) mRNA is a potential target of miR-134 regulation. CONCLUSIONS:These findings demonstrate a role for miR-134 in translation-dependent guidance of nerve growth cones. Different guidance cues may act through distinct signaling pathways to elicit PS-dependent and -independent mechanisms to steer growth cones in response to a wide array of spatiotemporal cues during development.

SUBMITTER: Han L

PROVIDER: S-EPMC3217933 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Regulation of chemotropic guidance of nerve growth cones by microRNA.

Han Liang L Wen Zhexing Z Lynn Rachel C RC Baudet Marie-Laure ML Holt Christine E CE Sasaki Yukio Y Bassell Gary J GJ Zheng James Q JQ

Molecular brain 20111103

<h4>Background</h4>The small non-coding microRNAs play an important role in development by regulating protein translation, but their involvement in axon guidance is unknown. Here, we investigated the role of microRNA-134 (miR-134) in chemotropic guidance of nerve growth cones.<h4>Results</h4>We found that miR-134 is highly expressed in the neural tube of Xenopus embryos. Fluorescent in situ hybridization also showed that miR-134 is enriched in the growth cones of Xenopus spinal neurons in cultur ...[more]

PMID: 22051374

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Project description:BackgroundChemotropic factors in the extracellular microenvironment guide nerve growth by acting on the growth cone located at the tip of extending axons. Growth cone extension requires the coordination of cytoskeleton-dependent membrane protrusion and dynamic adhesion to the extracellular matrix, yet how chemotropic factors regulate these events remains an outstanding question. We demonstrated previously that the inhibitory factor myelin-associated glycoprotein (MAG) triggers endocytic removal of the adhesion receptor ?1-integrin from the growth cone surface membrane to negatively remodel substrate adhesions during chemorepulsion. Here, we tested how a neurotrophin might affect integrin adhesions.ResultsWe report that brain-derived neurotropic factor (BDNF) positively regulates the formation of substrate adhesions in axonal growth cones during stimulated outgrowth and prevents removal of ?1-integrin adhesions by MAG. Treatment of Xenopus spinal neurons with BDNF rapidly triggered ?1-integrin clustering and induced the dynamic formation of nascent vinculin-containing adhesion complexes in the growth cone periphery. Both the formation of nascent ?1-integrin adhesions and the stimulation of axon extension by BDNF required cytoplasmic calcium ion signaling and integrin activation at the cell surface. Exposure to MAG decreased the number of ?1-integrin adhesions in the growth cone during inhibition of axon extension. In contrast, the BDNF-induced adhesions were resistant to negative remodeling by MAG, correlating with the ability of BDNF pretreatment to counteract MAG-inhibition of axon extension. Pre-exposure to MAG prevented the BDNF-induced formation of ?1-integrin adhesions and blocked the stimulation of axon extension by BDNF.ConclusionsAltogether, these findings demonstrate the neurotrophin-dependent formation of integrin-based adhesions in the growth cone and reveal how a positive regulator of substrate adhesions can block the negative remodeling and growth inhibitory effects of MAG. Such bidirectional remodeling may allow the growth cone to rapidly adjust adhesiveness to the extracellular matrix as a general mechanism for governing axon extension. Techniques for manipulating integrin internalization and activation state may be important for overcoming local inhibitory factors after traumatic injury or neurodegenerative disease to enhance regenerative nerve growth.

Project description:Understanding how plants respond to spaceflight and extraterrestrial environments is crucial to develop life-support systems intended for long-term human explorations. Gravity is a main factor influencing root development and orientation, typically masking other tropisms. Considering that reduced levels of gravity affect many plant responses in space, the interaction of other tropic stimuli in microgravity represents the frontier to be investigated aiming at life-support systems optimization. In this paper we report on MULTITROP (Multiple-Tropism: interaction of gravity, nutrient and water stimuli for root orientation in microgravity), an experiment performed on the International Space Station during the Expedition 52/53. Scientific aim of the experiment was to disentangle hydrotropism from chemotropism for root orientation in absence of the gravity stimulus. Among several species relevant to space farming, Daucus carota was selected for the experiment because of its suitability with the experimental hardware and setup. At launch site, carrot seeds were placed between two disks of inert substrate (one imbibed with water and the other with a disodium phosphate solution) and integrated into a hardware developed, refurbished and flight-certificated by Kayser Italia. Post-flight, a Ground Reference Experiment was performed. Root development and orientation of seedlings grown in microgravity and at 1g condition were measured through 3D-image analysis procedures after imaging with X-ray microtomography. Radicle protruded preferentially from the ventral side of the seed due to the asymmetric position of the embryo. Such a phenomenon did not prevent the achievement of MULTITROP scientific goal but should be considered for further experiments on radicle growth orientation in microgravity. The experiment conducted in space verified that the primary root of carrot shows a positive chemotropism towards disodium phosphate solution in the absence of the gravity stimulus. On Earth, the positive chemotropism was masked by the dominant effect of gravity and roots developed downward regardless of the presence/absence of nutrients in the substrate. Taking advantage of altered gravity conditions and using other chemical compounds, further studies should be performed to deepen our understanding of root chemotropic response and its interaction with other tropisms.

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Regulation of chemotropic guidance of nerve growth cones by microRNA.

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Regulation of chemotropic guidance of nerve growth cones by microRNA.

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