Suchergebnisse

Integrin function is regulated by activation involving conformational changes that modulate ligand-binding affinity and downstream signaling. Activation is regulated through inside-out signaling which is controlled by many signaling pathways via a final common pathway through kindlin and talin, which bind to the intracellular tail of beta integrins. Previous studies have shown that the axon growth inhibitory molecules NogoA and chondroitin sulfate proteoglycans (CSPGs) inactivate integrins. Overexpressing kindlin-1 in dorsal root ganglion (DRG) neurons activates integrins, enabling their axons to overcome inhibitory molecules in the environment, and promoting regeneration in vivo following dorsal root crush. Other studies have indicated that expression of the talin head alone or with kindlin can enhance integrin activation. Here, using adult rat DRG neurons, we investigate the effects of overexpressing various forms of talin on axon growth and integrin signaling. We found that overexpression of the talin head activated axonal integrins but inhibited downstream signaling via FAK, and did not promote axon growth. Similarly, co-expression of the talin head and kindlin-1 prevented the growth-promoting effect of kindlin-1, suggesting that the talin head acts as a form of dominant negative for integrin function. Using full-length talin constructs in PC12 cells we observed that neurite growth was enhanced by the expression of wild-type talin and more so by two 'activated' forms of talin produced by point mutation (on laminin and aggrecan-laminin substrates). Nevertheless, co-expression of full-length talin with kindlin did not promote neurite growth more than either molecule alone. In vivo, we find that talin is present in PNS axons (sciatic nerve), and also in CNS axons of the corticospinal tract. ; This work was funded by grants from the Medical Research Council (G1000864), the Henry Smith Charity, the Christopher and Dana Reeve Foundation, the John and Lucille van Geest Foundation, the European Union Framework 7 ...

Cultured neurons obtained from a hypomorphous MAP1B mutant mouse line display a selective and significant inhibition of axon formation that reflects a delay in axon outgrowth and a reduced rate of elongation. This phenomenon is paralleled by decreased microtubule formation and dynamics, which is dramatic at the distal axonal segment, as well as in growth cones, where the more recently assembled microtubule polymer normally predominates. These neurons also have aberrant growth cone formation and increased actin-based protrusive activity. Taken together, this study provides direct evidence showing that by promoting microtubule dynamics and regulating cytoskeletal organization MAP1B has a crucial role in axon formation. ; This work was supported by grants from the Spanish Direccion General de Investigacion Cientifica y Tecnica, Comunidad de Madrid, European Union, and an institutional grant from Formation de Recherche Associee to J.A. It was also supported by grants from Consejo Nacional de Investigaciones Cientificas y Tecnicas de Argentina (PICT-PIP 4906), FONCyT (PICT 05-00000-00937 and 99-5-6179), CONICOR, and a Howard Hughes Medical Institute Grant (HMMI 75197-553201) awarded under the International Research Scholars Program to A.C. An A.E.C.I./I.C.I. predoctoral fellowship was awarded to C.G.-B. The MAP1B mutant mouse was generated with financial support from Amgen and the Max Planck Society in the laboratory of Prof. P. Gruss. ; Peer reviewed

Objects The diffusion-based spherical mean technique (SMT) provides a novel model to relate multi-b-value diffusion magnetic resonance imaging (MRI) data to features of tissue microstructure. We propose the first clinical application of SMT to image the brain of patients with multiple sclerosis (MS) and investigate clinical feasibility and translation. Methods Eighteen MS patients and nine age- and sex-matched healthy controls (HCs) underwent a 3.0 Tesla scan inclusive of clinical sequences and SMT images (isotropic resolution of 2 mm). Axial diffusivity (AD), apparent axonal volume fraction (V-ax), and effective neural diffusivity (D-ax) parametric maps were fitted. Differences in AD, V-ax, and D-ax between anatomically matched regions reflecting different tissues types were estimated using generalized linear mixed models for binary outcomes. Results Differences were seen in all SMT-derived parameters between chronic black holes (cBHs) and T2-lesions (P <= 0.0016), in V-ax and AD between T2-lesions and normal appearing white matter (NAWM) (P < 0.0001), but not between the NAWM and normal WM in HCs. Inverse correlations were seen between V-ax and AD in cBHs (r = -0.750, P = 0.02); in T2-lesions D-ax values were associated with V-ax (r = 0.824, P < 0.0001) and AD (r = 0.570, P = 0.014). Interpretations SMT-derived metrics are sensitive to pathological changes and hold potential for clinical application in MS patients. ; Sources of support include: extramural program of the National Institutes of Health (NIH) (NIBIB K01 EB009120, R01 EB000461, and K25 EB013659), the Clinical and Translational Science Awards (UL1TR000445-06 from National Center for Advancing Translational Sciences/NIH), the European Union Horizon 2020 (EU H2020 634541-2), the EPSRC (Engineering and Physical Sciences Research Council), United Kingdom (UK) (UK EPSRC EP/M020533/1, UK EPSRC EP/N018702/1), the National MS Society (MS Clinical Mentorship Program, NMSS PP-180129686 and NMSS RG-1501-02840).

In the paper a (1 + 1)-dimension equation of motion for the artificial axon is considered. The artificial axon is a dynamical structure like a neuron. They are widely used in biophysics, for example, in studying the physiological processes. A topological non-trivial solution of one-kink type for this equation is constructed in an analytical form. The modified direct Hirota method for solving the nonlinear partial derivatives equations is applied. The special cases are considered for different voltages on the contacts of axon.

Abstract
Deafferentation is an important determinant of plastic changes in the CNS, which consists of a loss of inputs from the body periphery or from the CNS itself. Although cortical reorganization has been well documented, white matter plasticity was less explored. Our goal was to investigate microstructural interhemispheric connectivity changes in early and late amputated rats. For that purpose, we employed diffusion-weighted magnetic resonance imaging, as well as Western blotting, immunohistochemistry, and electron microscopy of sections of the white matter tracts to analyze the microstructural changes in the corticospinal tract and in the corpus callosum (CC) sector that contains somatosensory fibers integrating cortical areas representing the forelimbs and compare differences in rats undergoing forelimb amputation as neonates, with those amputated as adults. Results showed that early amputation induced decreased fractional anisotropy values and reduction of total myelin amount in the cerebral peduncle contralateral to the amputation. Both early and late forelimb amputations induced decreased myelination of callosal fibers. While early amputation affected myelination of thinner axons, late amputation disrupted axons of all calibers. Since the CC provides a modulation of inhibition and excitation between the hemispheres, we suggest that the demyelination observed among callosal fibers may misbalance this modulation.