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Laurence Decker

Publications and source records attributed to Laurence Decker.

9 recordsLinked to original sources
PubMed2006

Peripheral myelin maintenance is a dynamic process requiring constant Krox20 expression.

Onset of myelination in Schwann cells is governed by several transcription factors, including Krox20/Egr2, and mutations affecting Krox20 result in various human hereditary peripheral neuropathies, including congenital hypomyelinating neuropathy (CHN) and Charcot-Marie-Tooth disease (CMT). Similar molecular information is not available on the process of myelin maintenance. We have generated conditional Krox20 mutations in the mouse that allowed us to develop models for CHN and CMT. In the latter case, specific inactivation of Krox20 in adult Schwann cells results in severe demyelination, involving rapid Schwann cell dedifferentiation and increased proliferation, followed by an attempt to remyelinate and a block at the promyelinating stage. These data establish that Krox20 is not only required for the onset of myelination but that it is also crucial for the maintenance of the myelinating state. Furthermore, myelin maintenance appears as a very dynamic process in which Krox20 may constitute a molecular switch between Schwann cell myelination and demyelination programs.

Alleles↗
PubMed2005

Notch, epidermal growth factor receptor, and beta1-integrin pathways are coordinated in neural stem cells.

Notch1 and beta1-integrins are cell surface receptors involved in the recognition of the niche that surrounds stem cells through cell-cell and cell-extracellular matrix interactions, respectively. Notch1 is also involved in the control of cell fate choices in the developing central nervous system (Lewis, J. (1998) Semin. Cell Dev. Biol. 9, 583-589). Here we report that Notch and beta1-integrins are co-expressed and that these proteins cooperate with the epidermal growth factor receptor in neural progenitors. We describe data that suggests that beta1-integrins may affect Notch signaling through 1) physical interaction (sequestration) of the Notch intracellular domain fragment by the cytoplasmic tail of the beta1-integrin and 2) affecting trafficking of the Notch intracellular domain via caveolin-mediated mechanisms. Our findings suggest that caveolin 1-containing lipid rafts play a role in the coordination and coupling of beta1-integrin, Notch1, and tyrosine kinase receptor signaling pathways. We speculate that this will require the presence of the adequate beta1-activating extracellular matrix or growth factors in restricted regions of the central nervous system and namely in neurogenic niches.

Animals↗
PubMed2004

Lipid rafts and integrin activation regulate oligodendrocyte survival.

Newly formed oligodendrocytes in the CNS derive survival cues from their target axons. These cues are provided in part by laminins expressed on the axon, which are recognized by alpha6beta1 integrin on the oligdendrocyte and amplify platelet-derived growth factor (PDGF) signaling through the phosphatidylinositol 3'-kinase (PI3K) pathway. The alpha6beta1 integrin is localized in oligodendrocyte lipid rafts. We show here using the sphingolipid synthesis inhibitor fumonisin-B1 to deplete rafts that this localization is important for normal survival signaling, because depletion increases oligodendrocyte apoptosis and inhibits PI3K signaling. We have shown previously that PDGF-mediated integrin activation is an important component of oligodendrocyte proliferation signaling, and here we present evidence that a similar mechanism operates in survival signaling. Integrin activation using manganese increases raft localization and rescues the effects of both raft depletion and PDGF removal on survival and PI3K signaling. Together, these results point to an essential role for rafts in oligodendrocyte survival signaling on the basis of the provision of a favorable environment for growth factor-mediated integrin activation.

Animals↗
PubMed2003

Regulation of integrin growth factor interactions in oligodendrocytes by lipid raft microdomains.

Individual growth factors can regulate multiple aspects of behavior within a single cell during differentiation, with each signaling pathway controlled independently and also responsive to other receptors such as cell surface integrins. The mechanisms by which this is achieved remain poorly understood. Here we use myelin-forming oligodendrocytes and their precursors to examine the role of lipid rafts, cholesterol and sphingolipid-rich microdomains of the cell membrane implicated in cell signaling. In these cells, the growth factor PDGF has sequential and independent roles in proliferation and survival. We show that the oligodendrocyte PDGFalpha receptor becomes sequestered in a raft compartment at the developmental stage when PDGF ceases to promote proliferation, but is now required for survival. We also show that laminin-2, which is expressed on axons in the CNS and which provides a target-dependent signal for oligodendrocyte survival by amplification of PDGFalphaR signaling, induces clustering of the laminin binding integrin alpha6beta1 with the PDGFalphaR-containing lipid raft domains. This extracellular matrix-induced colocalization of integrin and growth factor receptor generates a signaling environment within the raft for survival-promoting PI3K/Akt activity. These results demonstrate novel signaling roles for lipid rafts that ensure the separation and amplification of growth factor signaling pathways during development.

Animals↗
PubMed2003

Myelin/oligodendrocyte glycoprotein-deficient (MOG-deficient) mice reveal lack of immune tolerance to MOG in wild-type mice.

We studied the immunological basis for the very potent encephalitogenicity of myelin/oligodendrocyte glycoprotein (MOG), a minor component of myelin in the CNS that is widely used to induce experimental autoimmune encephalomyelitis (EAE). For this purpose, we generated a mutant mouse lacking a functional mog gene. This MOG-deficient mouse presents no clinical or histological abnormalities, permitting us to directly assess the role of MOG as a target autoantigen in EAE. In contrast to WT mice, which developed severe EAE following immunization with whole myelin, MOG-deficient mice had a mild phenotype, demonstrating that the anti-MOG response is a major pathogenic component of the autoimmune response directed against myelin. Moreover, while MOG transcripts are expressed in lymphoid organs in minute amounts, both MOG-deficient and WT mice show similar T and B cell responses against the extracellular domain of MOG, including the immunodominant MOG 35-55 T cell epitope. Furthermore, no differences in the fine specificity of the T cell responses to overlapping peptides covering the complete mouse MOG sequence were observed between MOG+/+ and MOG-/- mice. In addition, upon adoptive transfer, MOG-specific T cells from WT mice and those from MOG-deficient mice are equally pathogenic. This total lack of immune tolerance to MOG in WT C57BL/6 mice may be responsible for the high pathogenicity of the anti-MOG immune response as well as the high susceptibility of most animal strains to MOG-induced EAE.

Animals↗
PubMed2002

Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice.

The destiny of the mitotically active cells of the subventricular zone (SVZ) in adult rodents is to migrate to the olfactory bulb, where they contribute to the replacement of granular and periglomerular neurons. However, these adult neural progenitors also can be mobilized in periventricular white matter and triggered to differentiate into astrocytes and oligodendrocytes in response to lysolecithin-induced demyelination. To mimic the environmental conditions of multiple sclerosis, we assessed the proliferation, migration, and differentiation potential of adult SVZ progenitor cells in response to experimental autoimmune encephalomyelitis (EAE) in mice. Inflammation and demyelination were observed in all mouse brains after EAE induction. EAE induced cell proliferation throughout the brain and especially within the lesions. Proliferating cells were neural progenitors, astrocytes, and oligodendrocyte precursors. EAE enhanced the migration of SVZ-derived neural progenitors to the olfactory bulb and triggered their mobilization in the periventricular white matter. The mobilized cells gave rise to neurons, astrocytes, and oligodendrocytes in the olfactory bulb but essentially to astrocytes and oligodendrocytes in the lesioned white matter. Our data indicate that the adult mouse SVZ is a source of newly generated oligodendrocytes and thus may contribute, along with oligodendrocyte precursors, to the replacement of oligodendrocytes in inflammatory demyelinating diseases of the central nervous system such as multiple sclerosis.

Animals↗
PubMed2002

Growth factor treatment promotes mobilization of young but not aged adult subventricular zone precursors in response to demyelination.

Precursor cells of the adult mouse subventricular zone (SVZ) are mobilized and recruited by a lysolecithin (LPC)-induced demyelination of the corpus callosum. Because age decreases the proliferation of the SVZ neural precursors as well as the potential for myelin repair of the adult central nervous system, we have compared the ability of young and aged adult neural precursors to respond to LPC-induced demyelination. With age, the SVZ cells lost their capacity to proliferate and to be recruited by the lesion. Whereas a single injection of fibroblast growth factor-2 or transforming growth factor-alpha stimulated the proliferation of SVZ and rostral migratory stream precursors in both groups of animals after demyelination, they favored recruitment at the lesion in young mice but not in aged ones. In vitro experiments using neurospheres derived from young and aged animals indicated that both populations have the same migratory performances. Our in vivo data thus suggest that aged neural precursors may loose their intrinsic capacities to respond to demyelination-induced signals. Alternatively, their function may be altered by modification of the aged extracellular environment.

Age Factors↗
PubMed2002

Loss of polysialic residues accelerates CNS neural precursor differentiation in pathological conditions.

Using the model of lysolecithin-induced demyelination of the corpus callosum in wild-type, NCAM-deficient, and endoneuraminidase-injected mice, we have analyzed the consequences of the loss of expression of NCAM or PSA residues on the migration and proliferation capacities of neural precursors of the subventricular zone (SVZ). We showed that the absence of PSA or NCAM delayed migration of neural precursors to the olfactory bulb and consequently enhanced their recruitment at the lesion site. Moreover, after demyelination, the lack of NCAM but not PSA promoted proliferation in the SVZ and the lesion while the lack of PSA favored the differentiation of the traced cells into the oligodendroglial fate both in the SVZ and in the lesion. As previously demonstrated in vitro (L. Decker et al., 2000, Mol. Cell. Neurosci. 16, 422-439), these data illustrate the involvement of PSA and NCAM in neural precursor motility and differentiation in the normal and injured central nervous system, suggesting distinct roles for these two molecules under pathophysiological conditions.

Animals↗