The mechanical control of nervous system development.

The development of the nervous system has so far, to a large extent, been considered in the context of biochemistry, molecular biology and genetics. However, there is growing evidence that many biological systems also integrate mechanical information when making decisions during differentiation, growth, proliferation, migration and general function. Based on recent findings, I hypothesize that several steps during nervous system development, including neural progenitor cell differentiation, neuronal migration, axon extension and the folding of the brain, rely on or are even driven by mechanical cues and forces.This work was supported by the Medical Research CouncilThis is the accepted version of the original publication available at http://dev.biologists.org/content/140/15/3069

Force Generation by Molecular-Motor-Powered Microtubule Bundles; Implications for Neuronal Polarization and Growth.

The heavily cross-linked microtubule (MT) bundles found in neuronal processes play a central role in the initiation, growth and maturation of axons and dendrites; however, a quantitative understanding of their mechanical function is still lacking. We here developed computer simulations to investigate the dynamics of force generation in 1D bundles of MTs that are cross-linked and powered by molecular motors. The motion of filaments and the forces they exert are investigated as a function of the motor type (unipolar or bipolar), MT density and length, applied load, and motor connectivity. We demonstrate that only unipolar motors (e.g., kinesin-1) can provide the driving force for bundle expansion, while bipolar motors (e.g., kinesin-5) oppose it. The force generation capacity of the bundles is shown to depend sharply on the fraction of unipolar motors due to a percolation transition that must occur in the bundle. Scaling laws between bundle length, force, MT length and motor fraction are presented. In addition, we investigate the dynamics of growth in the presence of a constant influx of MTs. Beyond a short equilibration period, the bundles grow linearly in time. In this growth regime, the bundle extends as one mass forward with most filaments sliding with the growth velocity. The growth velocity is shown to be dictated by the inward flux of MTs, to inversely scale with the load and to be independent of the free velocity of the motors. These findings provide important molecular-level insights into the mechanical function of the MT cytoskeleton in normal axon growth and regeneration after injury.We thank François Nédélec for his help with the Cytosim software and to Sarah Foster and Thomas Martin for proofreading. We are grateful to the UK Medical Research Council (Career Development Award to KF), the Israel Science Foundation (grant no. 1396/09 to AZ) and the Bonn Cologne Graduate School as well as Erasmus+ (MJ) for financial support.This is the final version of the article. It first appeared from Frontiers via http://dx.doi.org/10.3389/fncel.2015.0044

Theory for Durotactic Axon Guidance.

During the development of the nervous system, neurons extend bundles of axons that grow and meet other neurons to form the neuronal network. Robust guidance mechanisms are needed for these bundles to migrate and reach their functional target. Directional information depends on external cues such as chemical or mechanical gradients. Unlike chemotaxis that has been extensively studied, the role and mechanism of durotaxis, the directed response to variations in substrate rigidity, remain unclear. We model bundle migration and guidance by rigidity gradients by using the theory of morphoelastic rods. We show that, at a rigidity interface, the motion of axon bundles follows a simple behavior analogous to optic ray theory and obeys Snell's law for refraction and reflection. We use this powerful analogy to demonstrate that axons can be guided by the equivalent of optical lenses and fibers created by regions of different stiffnesses.ER

Mechanical Regulation of Neurite Polarization and Growth: A Computational Study.

The densely packed microtubule (MT) array found in neuronal cell projections (neurites) serves two fundamental functions simultaneously: it provides a mechanically stable track for molecular motor-based transport and produces forces that drive neurite growth. The local pattern of MT polarity along the neurite shaft has been found to differ between axons and dendrites. In axons, the neurons' dominating long projections, roughly 90% of the MTs orient with their rapidly growing plus end away from the cell body, whereas in vertebrate dendrites, their orientations are locally mixed. Molecular motors are known to be responsible for cytoskeletal ordering and force generation, but their collective function in the dense MT cytoskeleton of neurites remains elusive. We here hypothesized that both the polarity pattern of MTs along the neurite shaft and the shaft's global extension are simultaneously driven by molecular motor forces and should thus be regulated by the mechanical load acting on the MT array as a whole. To investigate this, we simulated cylindrical bundles of MTs that are cross-linked and powered by molecular motors by iteratively solving a set of force-balance equations. The bundles were subjected to a fixed load arising from actively generated tension in the actomyosin cortex enveloping the MTs. The magnitude of the load and the level of motor-induced connectivity between the MTs have been varied systematically. With an increasing load and decreasing motor-induced connectivity between MTs, the bundles became wider in cross section and extended more slowly, and the local MT orientational order was reduced. These results reveal two, to our knowledge, novel mechanical factors that may underlie the distinctive development of the MT cytoskeleton in axons and dendrites: the cross-linking level of MTs by motors and the load acting on this cytoskeleton during growth

Towards brain-tissue-like biomaterials

Many biomaterials have been developed which aim to match the elastic modulus of the brain for improved interfacing. However, other properties such as ultimate toughness, tensile strength, poroviscoelastic responses, energy dissipation, conductivity, and mass diffusivity also need to be considered

CNS cell distribution and axon orientation determine local spinal cord mechanical properties.

Mechanical signaling plays an important role in cell physiology and pathology. Many cell types, including neurons and glial cells, respond to the mechanical properties of their environment. Yet, for spinal cord tissue, data on tissue stiffness are sparse. To investigate the regional and direction-dependent mechanical properties of spinal cord tissue at a spatial resolution relevant to individual cells, we conducted atomic force microscopy (AFM) indentation and tensile measurements on acutely isolated mouse spinal cord tissue sectioned along the three major anatomical planes, and correlated local mechanical properties with the underlying cellular structures. Stiffness maps revealed that gray matter is significantly stiffer than white matter irrespective of directionality (transverse, coronal, and sagittal planes) and force direction (compression or tension) (K(g) = ∼ 130 P(a) vs. K(w) = ∼ 70 Pa); both matters stiffened with increasing strain. When all data were pooled for each plane, gray matter behaved like an isotropic material under compression; however, subregions of the gray matter were rather heterogeneous and anisotropic. For example, in sagittal sections the dorsal horn was significantly stiffer than the ventral horn. In contrast, white matter behaved transversely isotropic, with the elastic stiffness along the craniocaudal (i.e., longitudinal) axis being lower than perpendicular to it. The stiffness distributions we found under compression strongly correlated with the orientation of axons, the areas of cell nuclei, and cellular in plane proximity. Based on these morphological parameters, we developed a phenomenological model to estimate local mechanical properties of central nervous system (CNS) tissue. Our study may thus ultimately help predicting local tissue stiffness, and hence cell behavior in response to mechanical signaling under physiological and pathological conditions, purely based on histological data.The authors thank the CECAD Imaging Facility (and their staff members), Andreas Christ, Jochen Guck, Jolanta Kozlowski, Ryan MacDonald, Graham Sheridan, and Alex Winkel for helpful discussions and/or technical support. This work was supported by Köln Fortune Program/Faculty of Medicine, University of Cologne (Fellowship to D.E.K.), German National Academic Foundation (Scholarship to D.E.K.), Herchel Smith Foundation (Fellowship to E.M.), DAAD-PROMOS-Program (Scholarship to J.H.), Deutsche Forschungsgemeinschaft (grant KU2760/2-1 to S.K.), UK Medical Research Council (Career Development Award to K.F.), and the Human Frontier Science Program (Young Investigator Grant to K.F.).This is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.bpj.2015.03.03

Towards brain-tissue-like biomaterials

Many biomaterials have been developed which aim to match the elastic modulus of the brain for improved interfacing. However, other properties such as ultimate toughness, tensile strength, poroviscoelastic responses, energy dissipation, conductivity, and mass diffusivity also need to be considered

Development of the anterior-posterior axis is a self-organising process in the absence of maternal cues in mouse embryo

This work was supported by Wellcome Trust, Grant ID: 098287 (MZG) and EMBO (MB).This is the final version of the article. It first appeared from NPG via http://dx.doi.org/10.1038/cr.2015.10

Development of the anterior-posterior axis is a self-organizing process in the absence of maternal cues in the mouse embryo.

This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/cr.2015.104This work was supported by Wellcome Trust, Grant ID: 098287 (MZG) and EMBO (MB)