The inhibitory extracellular matrix in a spinal lesion site is a major impediment to axonal regeneration in mammals. In contrast, the extracellular matrix in zebrafish allows substantial axon ...re-growth, leading to recovery of movement. However, little is known about regulation and composition of the growth-promoting extracellular matrix. Here we demonstrate that activity of the Wnt/β-catenin pathway in fibroblast-like cells in the lesion site is pivotal for axon re-growth and functional recovery. Wnt/β-catenin signaling induces expression of col12a1a/b and deposition of Collagen XII, which is necessary for axons to actively navigate the non-neural lesion site environment. Overexpression of col12a1a rescues the effects of Wnt/β-catenin pathway inhibition and is sufficient to accelerate regeneration. We demonstrate that in a vertebrate of high regenerative capacity, Wnt/β-catenin signaling controls the composition of the lesion site extracellular matrix and we identify Collagen XII as a promoter of axonal regeneration. These findings imply that the Wnt/β-catenin pathway and Collagen XII may be targets for extracellular matrix manipulations in non-regenerating species.Following spinal injury in zebrafish, non-neural cells establish an extracellular matrix to promote axon re-growth but how this is regulated is unclear. Here, the authors show that Wnt/β-catenin signaling in fibroblast-like cells at a lesion activates axon re-growth via deposition of Collagen XII.
Coordinated development of brain stem and spinal target neurons is pivotal for the emergence of a precisely functioning locomotor system. Signals that match the development of these far-apart regions ...of the central nervous system may be redeployed during spinal cord regeneration. Here we show that descending dopaminergic projections from the brain promote motor neuron generation at the expense of V2 interneurons in the developing zebrafish spinal cord by activating the D4a receptor, which acts on the hedgehog pathway. Inhibiting this essential signal during early neurogenesis leads to a long-lasting reduction of motor neuron numbers and impaired motor responses of free-swimming larvae. Importantly, during successful spinal cord regeneration in adult zebrafish, endogenous dopamine promotes generation of spinal motor neurons, and dopamine agonists augment this process. Hence, we describe a supraspinal control mechanism for the development and regeneration of specific spinal cell types that uses dopamine as a signal.
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•Descending dopaminergic axons control neurogenesis in the ventral spinal cord•Dopamine promotes motor neuron generation at the expense of V2 neurons•Dopamine acts through the D4a receptor and hedgehog pathway•Dopamine promotes adult motor neuron regeneration
Dopaminergic axons descend from the brain and terminate in the spinal cord. Here, Reimer et al. show that dopamine release in the spinal cord promotes the production of motor neurons at the expense of V2 interneurons. This action is mediated by the hedgehog pathway via the D4a receptor.
Aim To measure the change in diagnostic accuracy of conventional film-screen mammography and full-field digital mammography (FFDM) with the addition of digital breast tomosynthesis (DBT) in women ...recalled for assessment following routine screening. Materials and methods Ethics approval for the study was granted. Women recalled for assessment following routine screening with screen-film mammography were invited to participate. Participants underwent bilateral, two-view FFDM and two-view DBT. Readers scored each lesion separately for probability of malignancy on screen-film mammography, FFDM, and then DBT. The scores were compared with the presence or absence of malignancy based on the final histopathology outcome. Results Seven hundred and thirty-eight women participated (93.2% recruitment rate). Following assessment 204 (26.8%) were diagnosed as malignant (147 invasive and 57 in-situ tumours), 286 (37.68%) as benign, and 269 (35.4%) as normal. The diagnostic accuracy was evaluated by using receiving operating characteristic (ROC) and measurement of area under the curve (AUC). The AUC values demonstrated a significant ( p = 0.0001) improvement in the diagnostic accuracy with the addition of DBT combined with FFDM and film-screen mammography (AUC = 0.9671) when compared to FFDM plus film-screen mammography (AUC = 0.8949) and film-screen mammography alone (AUC = 0.7882). The effect was significantly greater for soft-tissue lesions AUC was 0.9905 with the addition of DBT and AUC was 0.9201 for FFDM with film-screen mammography combined ( p = 0.0001) compared to microcalcification with the addition of DBT (AUC = 0.7920) and for FFDM with film-screen mammography combined (AUC = 0.7843; p = 0.3182). Conclusion The addition of DBT increases the accuracy of mammography compared to FFDM and film-screen mammography combined and film-screen mammography alone in the assessment of screen-detected soft-tissue mammographic abnormalities.
In contrast to mammals, zebrafish regenerate spinal motor neurons. During regeneration, developmental signals are re-deployed. Here, we show that, during development, diffuse serotonin promotes ...spinal motor neuron generation from pMN progenitor cells, leaving interneuron numbers unchanged. Pharmacological manipulations and receptor knockdown indicate that serotonin acts at least in part via 5-HT1A receptors. In adults, serotonin is supplied to the spinal cord mainly (90%) by descending axons from the brain. After a spinal lesion, serotonergic axons degenerate caudal to the lesion but sprout rostral to it. Toxin-mediated ablation of serotonergic axons also rostral to the lesion impaired regeneration of motor neurons only there. Conversely, intraperitoneal serotonin injections doubled numbers of new motor neurons and proliferating pMN-like progenitors caudal to the lesion. Regeneration of spinal-intrinsic serotonergic interneurons was unaltered by these manipulations. Hence, serotonin selectively promotes the development and adult regeneration of motor neurons in zebrafish.
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•Serotonin is a remote signal promoting motor neuron regeneration in adult zebrafish•Serotonin acts on proliferation of pMN-like progenitors•Serotonin does not affect regeneration of spinal serotonergic neurons•Exogenous serotonin can compensate for the loss of endogenous serotonergic axons
Adult zebrafish, in contrast to mammals, regenerate spinal neurons. Barreiro-Iglesias et al. establish that serotonin from descending axons promotes the regeneration of motor neurons in the lesioned spinal cord but leaves spinal serotonergic neuron regeneration unaffected. Serotonin acts specifically on adult progenitor cells for motor neurons.
Chronic cerebral hypoperfusion, a sustained modest reduction in cerebral blood flow, is associated with damage to myelinated axons and cognitive decline with ageing. Oligodendrocytes (the myelin ...producing cells) and their precursor cells (OPCs) may be vulnerable to the effects of hypoperfusion and in some forms of injury OPCs have the potential to respond and repair damage by increased proliferation and differentiation. Using a mouse model of cerebral hypoperfusion we have characterised the acute and long term responses of oligodendrocytes and OPCs to hypoperfusion in the corpus callosum. Following 3 days of hypoperfusion, numbers of OPCs and mature oligodendrocytes were significantly decreased compared to controls. However following 1 month of hypoperfusion, the OPC pool was restored and increased numbers of oligodendrocytes were observed. Assessment of proliferation using PCNA showed no significant differences between groups at either time point but showed reduced numbers of proliferating oligodendroglia at 3 days consistent with the loss of OPCs. Cumulative BrdU labelling experiments revealed higher numbers of proliferating cells in hypoperfused animals compared to controls and showed a proportion of these newly generated cells had differentiated into oligodendrocytes in a subset of animals. Expression of GPR17, a receptor important for the regulation of OPC differentiation following injury, was decreased following short term hypoperfusion. Despite changes to oligodendrocyte numbers there were no changes to the myelin sheath as revealed by ultrastructural assessment and fluoromyelin however axon-glial integrity was disrupted after both 3 days and 1 month hypoperfusion. Taken together, our results demonstrate the initial vulnerability of oligodendroglial pools to modest reductions in blood flow and highlight the regenerative capacity of these cells.
Motor Neuron Regeneration in Adult Zebrafish Reimer, Michell M; Sorensen, Inga; Kuscha, Veronika ...
The Journal of neuroscience,
08/2008, Letnik:
28, Številka:
34
Journal Article
Recenzirano
Odprti dostop
The mammalian spinal cord does not regenerate motor neurons that are lost as a result of injury or disease. Here we demonstrate that adult zebrafish, which show functional spinal cord regeneration, ...are capable of motor neuron regeneration. After a spinal lesion, the ventricular zone shows a widespread increase in proliferation, including slowly proliferating olig2-positive (olig2+) ependymo-radial glial progenitor cells. Lineage tracing in olig2:green fluorescent protein transgenic fish indicates that these cells switch from a gliogenic phenotype to motor neuron production. Numbers of undifferentiated small HB9+ and islet-1+ motor neurons, which are double labeled with the proliferation marker 5-bromo-2-deoxyuridine (BrdU), are transiently strongly increased in the lesioned spinal cord. Large differentiated motor neurons, which are lost after a lesion, reappear at 6-8 weeks after lesion, and we detected ChAT+/BrdU+ motor neurons that were covered by contacts immunopositive for the synaptic marker SV2. These observations suggest that, after a lesion, plasticity of olig2+ progenitor cells may allow them to generate motor neurons, some of which exhibit markers for terminal differentiation and integration into the existing adult spinal circuitry.
Digital breast tomosynthesis (DBT) is a modified mammographic technique that overcomes some of the limitations of full-field digital mammography (2DDM) by eliminating the effect of overlapping breast ...tissue. In the UK, DBT is utilised in both the symptomatic setting and in breast screening assessment clinics. A literature search was conducted from 2010–2017 to ensure that the most recent developments in DBT technology, clinical applications, and assessment of its usefulness in breast screening were reviewed. Technological advances in DBT include the addition of synthetic 2D mammograms, which are generated from the DBT data set, and the use of DBT to guide vacuum-assisted biopsy and excisions. The units from each vendor vary in several aspects, which are detailed in this article. DBT improves diagnostic accuracy and reader confidence when identifying benign and malignant lesions. It has also been shown to be more accurate than 2DDM in assessing tumour size and in the assessment of multifocal tumours. In the screening setting, retrospective reader studies have shown that the addition of DBT to 2DDM showed equivalent or an improvement in sensitivity and specificity when compared to 2DDM alone. Many of these trials showed an increase in invasive cancer detection and a reduction in recall rates. Large prospective randomised controlled trials conducted in Europe and North America will evaluate effectiveness, practicalities, and cost implications of utilising DBT in routine breast screening practice.
The development of bio-based materials has been a consequence of the environmental awareness generated over time. The versatility of native starch is a promising starting point for manufacturing ...environmentally friendly materials. This work aims to compile information on the advancements in research on thermoplastic starch (TPS) nanocomposites after the addition of mainly these four nanofillers: natural montmorillonite (MMT), organically modified montmorillonite (O-MMT), cellulose nanocrystals (CNC), and cellulose nanofibers (CNF). The analyzed properties of nanocomposites were mechanical, barrier, optical, and degradability. The most important results were that as the nanofiller increases, the TPS modulus and strength increase; however, the elongation decreases. Furthermore, the barrier properties indicate that that the incorporation of nanofillers confers superior hydrophobicity. However, the optical properties (transparency and luminosity) are mostly reduced, and the color variation is more evident with the addition of these fillers. The biodegradability rate increases with these nanocompounds, as demonstrated by the study of the method of burial in the soil. The results of this compilation show that the compatibility, proper dispersion, and distribution of nanofiller through the TPS matrix are critical factors in overcoming the limitations of starch when extending the applications of these biomaterials. TPS nanocomposites are materials with great potential for improvement. Exploring new sources of starch and natural nano-reinforcement could lead to a genuinely eco-friendly material that can replace traditional polymers in applications such as packaging.
Myelinated axons have a distinct protein architecture essential for action potential propagation, neuronal communication, and maintaining cognitive function. Damage to myelinated axons, associated ...with cerebral hypoperfusion, contributes to age-related cognitive decline. We sought to determine early alterations in the protein architecture of myelinated axons and potential mechanisms after hypoperfusion. Using a mouse model of hypoperfusion, we assessed changes in proteins critical to the maintenance of paranodes, nodes of Ranvier, axon-glial integrity, axons, and myelin by confocal laser scanning microscopy. As early as 3 d after hypoperfusion, the paranodal septate-like junctions were damaged. This was marked by a progressive reduction of paranodal Neurofascin signal and a loss of septate-like junctions. Concurrent with paranodal disruption, there was a significant increase in nodal length, identified by Nav1.6 staining, with hypoperfusion. Disruption of axon-glial integrity was also determined after hypoperfusion by changes in the spatial distribution of myelin-associated glycoprotein staining. These nodal/paranodal changes were more pronounced after 1 month of hypoperfusion. In contrast, the nodal anchoring proteins AnkyrinG and Neurofascin 186 were unchanged and there were no overt changes in axonal and myelin integrity with hypoperfusion. A microarray analysis of white matter samples indicated that there were significant alterations in 129 genes. Subsequent analysis indicated alterations in biological pathways, including inflammatory responses, cytokine-cytokine receptor interactions, blood vessel development, and cell proliferation processes. Our results demonstrate that hypoperfusion leads to a rapid disruption of key proteins critical to the stability of the axon-glial connection that is mediated by a diversity of molecular events.
The MECOM gene encodes multiple protein isoforms that are essential for hematopoietic stem cell self-renewal and maintenance. Germline MECOM variants have been associated with congenital ...thrombocytopenia, radioulnar synostosis and bone marrow failure; however, the phenotypic spectrum of MECOM-associated syndromes continues to expand and novel pathogenic variants continue to be identified. We describe eight unrelated patients who add to the previously known phenotypes and genetic defects of MECOM-associated syndromes. As each subject presented with unique MECOM variants, the series failed to demonstrate clear genotype-to-phenotype correlation but may suggest a role for additional modifiers that affect gene expression and subsequent phenotype. Recognition of the expanded hematologic and non-hematologic clinical features allows for rapid molecular diagnosis, early identification of life-threatening complications, and improved genetic counseling for families. A centralized international publicly accessible database to share annotated MECOM variants would advance their clinical interpretation and provide a foundation to perform functional MECOM studies.
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