Recherches expérimentales sur la souche S.F.A. du virus suipestique lapinisé

Mackowiak Czesław, Leftheriotis E., Camand R., Goret Pierre. Recherches expérimentales sur la Souche S. F. A. du virus suipestique lapinisé . In: Bulletin de l'Académie Vétérinaire de France tome 110 n°7, 1957. pp. 307-314

Role of the lesion scar in the response to damage and repair of the central nervous system

Traumatic damage to the central nervous system (CNS) destroys the blood-brain barrier (BBB) and provokes the invasion of hematogenous cells into the neural tissue. Invading leukocytes, macrophages and lymphocytes secrete various cytokines that induce an inflammatory reaction in the injured CNS and result in local neural degeneration, formation of a cystic cavity and activation of glial cells around the lesion site. As a consequence of these processes, two types of scarring tissue are formed in the lesion site. One is a glial scar that consists in reactive astrocytes, reactive microglia and glial precursor cells. The other is a fibrotic scar formed by fibroblasts, which have invaded the lesion site from adjacent meningeal and perivascular cells. At the interface, the reactive astrocytes and the fibroblasts interact to form an organized tissue, the glia limitans. The astrocytic reaction has a protective role by reconstituting the BBB, preventing neuronal degeneration and limiting the spread of damage. While much attention has been paid to the inhibitory effects of the astrocytic component of the scars on axon regeneration, this review will cover a number of recent studies in which manipulations of the fibroblastic component of the scar by reagents, such as blockers of collagen synthesis have been found to be beneficial for axon regeneration. To what extent these changes in the fibroblasts act via subsequent downstream actions on the astrocytes remains for future investigation

Expression of netrin-1, slit-1 and slit-3 but not of slit-2 after cerebellar and spinal cord lesions.

To determine whether members of the Netrin-1 and Slit families and their receptors are expressed after central nervous system (CNS) injury, we performed in situ hybridization for netrin-1, slit-1, 2 and 3, and their receptors (dcc, unc5h-1, 2 and 3, robo-1, 2 and 3) 8 days, 2-3 months and 12-18 months after traumatic lesions of rat cerebellum. The expression pattern of these molecules was unchanged in axotomized Purkinje cells, whereas unc5h3 expression was upregulated in deafferented granule cells. Cells expressing slit-2 or dcc were never detected at the lesion site. By contrast, cells expressing netrin-1, slit-1 and slit-3, unc5h-1, 2 and 3, and robo-1, 2 and 3 (rig-1) could be detected at the cerebellar lesion site as soon as 8 days after injury. Expression of unc5h-2, robo-1, robo-2, slit-1 and slit-3 at the lesion site was maintained until 3 months, and up to 12-18 months for unc5h-1 and 3 and robo-3. Likewise, in the mouse spinal cord, netrin-1, slit-1 and slit-3 were also expressed at the lesion site 8 days after injury. Most of the cells expressing these mRNAs were located at the centre of the lesions, suggesting that they are macrophages/activated microglial cells (macrophagic cells) or meningeal fibroblastic cells. The macrophagic nature of most Netrin-1-positive cells and the macrophagic or fibroblastic nature of Robo-1-positive cells were corroborated by double staining. Thus, Netrin-1, Slits and their receptors may contribute to the regenerative failure of axons in the adult CNS by inhibiting axon outgrowth or by participating in the formation of the CNS scar

Cell death and axon regeneration of Purkinje cells after axotomy: challenges of classical hypotheses of axon regeneration.

Although adult mammalian neurons are able to regenerate their axons in the peripheral nervous system under certain conditions, they are not able to do it in the central nervous system. The environment surrounding the severed axons appears to be a key factor for axon regeneration. Many studies aiming to enhance axon regeneration in the CNS of adult mammals have successfully manipulated this environment by adding growth permissive molecules and/or neutralizing growth inhibitory molecules. In both cases, the number of axons able to regenerate was low and the different neuronal populations were not equal in their regenerative response, suggesting that manipulation of the environment is not always sufficient. This is particularly well illustrated in the cerebellar system, in which axotomized inferior olivary neurons regenerate when confronted with a permissive environment, whereas mature Purkinje cells do not. The intrinsic ability of a neuron to regenerate its axon is generally correlated with the intensity of its reaction to axotomy (expression of molecules, probability to die). Furthermore, molecules such as GAP-43 (growth-associated molecule) and c-Jun are involved in both axon regeneration and cell death suggesting that these two processes are linked. Surprisingly, Purkinje cells lose their capacity to regenerate their axon (even in the absence of myelin) during development before losing their capacity to react to an axotomy by cell death. These results emphasize the different reactions to axotomy between neuron types and underline that in Purkinje cells, the two cell decisions (axon regeneration and cell death) are differently regulated and therefore not part of the same signaling pathway

The transmembrane semaphorin Sema4D/CD100, an inhibitor of axonal growth, is expressed on oligodendrocytes and upregulated after CNS lesion.

Semaphorins are a family of secreted and membrane-bound proteins, known to regulate axonal pathfinding. Sema4D, also called CD100, was first isolated in the immune system where it is involved in B and T cell activation. We found that in the mouse, Sema4D is expressed in cells throughout the CNS white matter, with a peak during the myelination period. Double-labeling experiments with different markers of oligodendrocyte lineage such as olig1, olig2, platelet-derived growth factor receptor alpha, and proteolipid protein showed that Sema4D was expressed selectively by oligodendrocytes and myelin. The presence of Sema4D in myelin was confirmed using Western blot. Sema4D expression in myelinating oligodendrocytes was further observed using neuron-oligodendrocyte cocultures. Moreover, using stripe assay, we found that Sema4D is strongly inhibitory for postnatal sensory and cerebellar granule cell axons. This prompted us to examine whether Sema4D expression is modified after CNS injury. At 8 d after spinal cord lesions, Sema4D expression was strongly upregulated in oligodendrocytes at the periphery of the lesion. Sema4D-positive cells were not colabeled with the astrocyte marker GFAP, with the microglial and macrophagic marker isolectin B4, or with NG2, a marker of oligodendrocyte precursors. This upregulation was transient because from 1 month after the lesion, Sema4D expression was back to its normal level. These results indicate that Sema4D is a novel inhibitory factor for axonal regeneration expressed in myelin

Adherens junction treadmilling during collective migration

Comment in Retrograde flow of cadherins in collective cell migration. Hirata E, Park D, Sahai E. Nat Cell Biol. 2014 Jul;16(7):621-3. doi: 10.1038/ncb2995. PMID: 24981633International audienceCollective cell migration is essential for both physiological and pathological processes. Adherens junctions (AJs) maintain the integrity of the migrating cell group and promote cell coordination while allowing cellular rearrangements. Here, we show that AJs undergo a continuous treadmilling along the lateral sides of adjacent leading cells. The treadmilling is driven by an actin-dependent rearward movement of AJs and is supported by the polarized recycling of N-cadherin. N-cadherin is mainly internalized at the cell rear and then recycled to the leading edge where it accumulates before being incorporated into forming AJs at the front of lateral cell-cell contacts. The polarized dynamics of AJs is controlled by a front-to-rear gradient of p120-catenin phosphorylation, which regulates polarized trafficking of N-cadherin. Perturbation of the GSK3-dependent phosphorylation of p120-catenin impacts on the stability of AJs, and the polarity and speed of leading cells during collective migratio