Denervated Schwann cells attract macrophages by secretion of leukemia inhibitory factor (LIF) and monocyte chemoattractant protein-1 in a process regulated by interleukin-6 and LIF

Injury to peripheral nerves results in the infiltration of immune cells, which remove axonal- and myelin-derived material. Schwann cells could play a key role in this process by regulating macrophage infiltration. We show here that medium conditioned by primary denervated Schwann cells or the Schwannoma cell line RN22 produces chemotactic activity for macrophages. The presence of blocking antibodies to macrophage chemoattractant protein-1 (MCP-1) or leukemia inhibitory factor (LIF) reduced this activity to similar to35 and 65% of control levels, respectively, and only 15% remained in the presence of both antibodies. The presence of chemotactic LIF in Schwann cell-conditioned medium was confirmed by using cells from lif-/- mice. Although interleukin-6 (IL-6) is not itself a chemotactic factor, we found that medium from il-6-/- nerves showed only 40% of the activity secreted by wild-type nerves. Furthermore, IL-6 rapidly induced LIF mRNA in primary Schwann cells, and LIF rapidly induced MCP-1 mRNA expression. Treatment of RN22 Schwannoma cells with IL-6 or LIF enhanced the secretion of the chemotactic activity of these cells.These observations show that Schwann cells attract macrophages by secreting MCP-1 and LIF. They also provide evidence for an autocrine-signaling cascade involving IL-6, LIF, and MCP-1, which amplifies the Schwann cell-derived chemotactic signals gradually, in agreement with the delayed entry of macrophages to injured nerves

Genomic function during the lampbrush chromosome stage of amphibian oogenesis

Throughout its lengthy developmental history the disposition of the genetic material in the amphibian oocyte nucleus differs from that in other cell types. The chromosomes in the oocyte nucleus, arrested for the whole of oogenesis at the prophase of the first meiotic division, are known to contain at least the tetraploid amount of DNA.(1,2) Oogenesis in amphibia requires months or even years to complete, depending on the species

The repair Schwann cell and its function in regenerating nerves.

Nerve injury triggers the conversion of myelin and non-myelin (Remak) Schwann cells to a cell phenotype specialised to promote repair. Distal to damage, these repair Schwann cells provide the necessary signals and spatial cues for the survival of injured neurons, axonal regeneration and target reinnervation. The conversion to repair Schwann cells involves de-differentiation together with alternative differentiation, or activation, a combination that is typical of cell type conversions often referred to as (direct or lineage) reprogramming. Thus, injury-induced Schwann cell reprogramming involves down-regulation of myelin genes combined with activation of set of repair-supportive features, including up-regulation of trophic factors, elevation of cytokines as part of the innate immune response, myelin clearance by activation of myelin autophagy in Schwann cells and macrophage recruitment, and the formation of regeneration tracks, Bungner's bands, for directing axons to their targets. This repair program is controlled transcriptionally by mechanisms involving the transcription factor c-Jun, which is rapidly up-regulated in Schwann cells after injury. In the absence of c-Jun, damage results in the formation of a dysfunctional repair cell, neuronal death and failure of functional recovery. c-Jun, although not required for Schwann cell development, is therefore central to the reprogramming of myelin and non-myelin (Remak) Schwann cells to repair cells after injury. In future, the signalling that specifies this cell requires further analysis so that pharmacological tools that boost and maintain the repair Schwann cell phenotype can be developed. This article is protected by copyright. All rights reserved

TGF beta type II receptor signaling controls Schwann cell death and proliferation in developing nerves

During development, Schwann cell numbers are precisely adjusted to match the number of axons. It is essentially unknown which growth factors or receptors carry out this important control in vivo. Here, we tested whether the type II transforming growth factor (TGF)beta receptor has a role in this process. We generated a conditional knock-out mouse in which the type II TGF beta receptor is specifically ablated only in Schwann cells. Inactivation of the receptor, evident at least from embryonic day 18, resulted in suppressed Schwann cell death in normally developing and injured nerves. Notably, the mutants also showed a strong reduction in Schwann cell proliferation. Consequently, Schwann cell numbers in wild-type and mutant nerves remained similar. Lack of TGF beta signaling did not appear to affect other processes in which TGF beta had been implicated previously, including myelination and response of adult nerves to injury. This is the first in vivo evidence for a growth factor receptor involved in promoting Schwann cell division during development and the first genetic evidence for a receptor that controls normal developmental Schwann cell death

The structural and functional integrity of peripheral nerves depends on the glial-derived signal desert hedgehog

We show that desert hedgehog ( dhh), a signaling molecule expressed by Schwann cells, is essential for the structural and functional integrity of the peripheral nerve. Dhh-null nerves display multiple abnormalities that affect myelinating and nonmyelinating Schwann cells, axons, and vasculature and immune cells. Myelinated fibers of these mice have a significantly increased ( more than two times) number of Schmidt-Lanterman incisures ( SLIs), and connexin 29, a molecular component of SLIs, is strongly upregulated. Crossing dhh-null mice with myelin basic protein ( MBP)-deficient shiverer mice, which also have increased SLI numbers, results in further increased SLIs, suggesting that Dhh and MBP control SLIs by different mechanisms. Unmyelinated fibers are also affected, containing many fewer axons per Schwann cell in transverse profiles, whereas the total number of unmyelinated axons is reduced by approximately one-third. In dhh-null mice, the blood-nerve barrier is permeable and neutrophils and macrophage numbers are elevated, even in uninjured nerves. Dhh-null nerves also lack the largest-diameter myelinated fibers, have elevated numbers of degenerating myelinated axons, and contain regenerating fibers. Transected dhh nerves degenerate faster than wild-type controls. This demonstrates that a single identified glial signal, Dhh, plays a critical role in controlling the integrity of peripheral nervous tissue, in line with its critical role in nerve sheath development ( Parmantier et al., 1999). The complexity of the defects raises a number of important questions about the Dhh-dependent cell-cell signaling network in peripheral nerves

Evidence for prelocalization of cytoplasmic factors affecting gene activation in early embryogenesis

Differentiation begins early in embryogenesis as different genes become active in different cells. Within the closed system of the early embryo, equal genomes thus direct the creation of diverse cell types. Though the nuclei of these cells contain complete copies of the same genome,(1,2) the nucleoplasmic and cytoplasmic environments of these genomes are not the same, as a result of the distribution of cleavage nuclei into diverse areas of egg cytoplasm early in the cleavage process. In some cases the fate of these nuclei, i.e., the type of differentiated cell to which they or their descendants give rise, has been seen to depend on the area of cytoplasm in which they come to lie

Transforming growth factor beta (TGF beta) mediates schwann cell death in vitro and in vivo: Examination of c-jun activation, interactions with survival signals, and the relationship of TGF beta-mediated death to schwann cell differentiation

In some situations, cell death in the nervous system is controlled by an interplay between survival factors and negative survival signals that actively induce apoptosis. The present work indicates that the survival of Schwann cells is regulated by such a dual mechanism involving the negative survival signal transforming growth factor beta (TGF beta), a family of growth factors that is present in the Schwann cells themselves. We analyze the interactions between this putative autocrine death signal and previously defined paracrine and autocrine survival signals and show that expression of a dominant negative c-Jun inhibits TGF beta -induced apoptosis. This and other findings pinpoint activation of c-Jun as a key downstream event in TGF beta -induced Schwann cell death. The ability of TGF beta to kill Schwann cells, like normal Schwann cell death in vivo, is under a strong developmental regulation, and we show that the decreasing ability of TGF beta to kill older cells is attributable to a decreasing ability of TGF beta to phosphorylate c-Jun in more differentiated cells

PCA by Determinant Optimization has no Spurious Local Optima

Principal component analysis (PCA) is an indispensable tool in many learning tasks that finds the best linear representation for data. Classically, principal components of a dataset are interpreted as the directions that preserve most of its "energy", an interpretation that is theoretically underpinned by the celebrated Eckart-Young-Mirsky Theorem. There are yet other ways of interpreting PCA that are rarely exploited in practice, largely because it is not known how to reliably solve the corresponding non-convex optimisation programs. In this paper, we consider one such interpretation of principal components as the directions that preserve most of the "volume" of the dataset. Our main contribution is a theorem that shows that the corresponding non-convex program has no spurious local optima. We apply a number of solvers for empirical confirmation

Ageing and the Regulation of Cell Activities during Exposure to Cold

The inability to maintain body temperature and a selective pattern of changes in the regulation of cell activities were revealed by briefly exposing ageing C57B1/6J male mice to cold (10°C). The induction of liver tyrosine aminotransferase (TAT) during exposure to cold (a gene-dependent process) was markedly delayed in senescent mice (26 months old) as compared with younger mice (3–16 months old); after the delay, the rate of increase of TAT was similar to that prevailing in younger mice. Direct challenge of the liver with injections of corticosterone or insulin elicited the induction of TAT on an identical time course in young and senescent mice. These experiments provide an example of an age change in a gene-dependent cell process (the delayed induction of TAT in senescent mice during exposure to cold) which is not due to a change in the potential of the genome for responding when exogenous stimulae are supplied (injection of hormones). In contrast to the age-related change in liver cell activities, no significant changes were found in the secretion of corticosterone during exposure to cold. Although the seat of these selective age-related changes in the regulation of cell activities remains unclear, it is argued that generalized damage to the genome of cells throughout the body is not involved. The results of this and other studies showing the selective effect of age on cell activities are considered in terms of the concept that many cellular age changes represent the response of cells to primary age-related changes in humoral factors in the internal environment of the body