N-Cadherin Mediates Neuronal Cell Survival through Bim Down-Regulation

University of Illinois at Chicago, United States of America
PLoS ONE (Impact Factor: 3.23). 03/2012; 7(3):e33206. DOI: 10.1371/journal.pone.0033206
Source: PubMed


N-cadherin is a major adhesion molecule involved in the development and plasticity of the nervous system. N-cadherin-mediated cell adhesion regulates neuroepithelial cell polarity, neuronal precursor migration, growth cone migration and synaptic plasticity. In vitro, it has been involved in signaling events regulating processes such as cell mobility, proliferation and differentiation. N-cadherin has also been implicated in adhesion-dependent protection against apoptosis in non-neuronal cells. In this study, we investigated if the engagement of N-cadherin participates to the control of neuronal cells survival/death balance. We observed that plating either primary mouse spinal cord neurons or primary rat hippocampal neurons on N-cadherin recombinant substrate greatly enhances their survival compared to non-specific adhesion on poly-L-lysine. We show that N-cadherin engagement, in the absence of other survival factors (cell-matrix interactions and serum), protects GT1-7 neuronal cells against apoptosis. Using this cell line, we then searched for the signaling pathways involved in the survival effect of N-cadherin engagement. The PI3-kinase/Akt survival pathway and its downstream effector Bad are not involved, as no phosphorylation of Akt or Bad proteins in response to N-cadherin engagement was observed. In contrast, N-cadherin engagement activated the Erk1/2 MAP kinase pathway. Moreover, N-cadherin ligation mediated a 2-fold decrease in the level of the pro-apoptotic protein Bim-EL whereas the level of the anti-apoptotic protein Bcl-2 was unchanged. Inhibition of Mek1/2 kinases with U0126, and the resulting inhibition of Erk1/2 phosphorylation, induced the increase of both the level of Bim-EL and apoptosis of cells seeded on the N-cadherin substrate, suggesting that Erk phosphorylation is necessary for cell survival. Finally, the overexpression of a phosphorylation defective form of Bim-EL prevented N-cadherin-engagement induced cell survival. In conclusion, our results show that N-cadherin engagement mediates neuronal cell survival by enhancing the MAP kinase pathway and down-regulating the pro-apoptotic protein Bim-EL.

Download full-text


Available from: Charlotte Plestant, May 19, 2014
  • Source
    • "The binding of MT and EmtinB to megalin and to the low-density lipoprotein receptor-related protein 1 (LRP), activated the extracellular signal-regulated kinases (ERK), Akt, and cAMP response element-binding (CREB) [134] (Fig. 2). Since Akt and ERK are involved in the promotion of neuronal survival and differentiation [136], these signaling cascades might underlie the survivalpromoting effect of MT and EmtinB in vitro and, at least partially, the neuroprotective effect of EmtinB in vivo. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Metallothioneins (MT) are a family of proteins actively involved in metal detoxification and storage as well as in prevention of free-radical damage. Changes in the levels of MT have been described in a number of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, prion protein disease, Binswanger type of subcortical vascular dementia, and amyotrophic lateral sclerosis. This suggests that MT functions might be more complex and vast than what was initially thought. In this review, we summarize the current knowledge on the potential involvement of MT in the mentioned neurodegenerative diseases while also discussing the emerging evidence proposing MT modulation as a feasible therapeutic approach. Enhancing repair mechanisms after neurological damage and/or protection against oxidative stress through a proper modulation of this family of protein might indeed represent an important avenue to cope neurodegeneration.
    Full-text · Article · Feb 2014 · Journal of Alzheimer's disease: JAD
  • Source
    • "We also considered the possibility that NCAD deletion increased neuronal death thereby indirectly affecting growth. Therefore, in our neurite outgrowth assay we also examined DAPI-stained neuronal nuclei for hallmarks of apoptosis, as has been done previously [14] [25]. We found evidence of neuronal apoptosis in 18% of DRG neurons grown on NCAD-expressing astrocytes and 11% of NCAD-deficient astrocytes (p = 0.32), suggesting deletion of NCAD did not affect DRG neuron death in these cultures. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We examined the neurite outgrowth of sensory neurons on astrocytes following the genetic deletion of N-cadherin (NCAD). Deletion abolished immunostaining for NCAD and the other classical cadherins, indicating that NCAD is likely the only classical cadherin expressed by astrocytes. Only 38% of neurons grown on NCAD-deficient astrocytes for 24 h produced neurites, as compared to 74% of neurons grown on NCAD-expressing astrocytes. Of the neurons that produced neurites, those grown on NCAD-deficient astrocytes had a mean total length of 378 μm, as compared to 1093 μm for neurons grown on NCAD-expressing astrocytes. Thus, the loss of NCAD greatly impairs the formation and extension neurites on astrocytes.
    Full-text · Article · Jun 2012 · Neuroscience Letters
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Spheroid models have led to an increased understanding of differentiation, tissue organization and homeostasis. In the present study, we have observed that under a serum-free medium, human dental pulp cells (DPCs) spontaneously formed spheroids, and could survive over 15 weeks. To characterize these spheroids, we investigated their dynamics, microenvironment, cell distribution, molecular profiles and neuronal/osteogenic potential. Cell tracking assay showed that cells inside the spheroids have very slow cycling. Although the spheroids had hypoxia microenvironments, there were not any massive cell die-offs even after long-term cultivation. Whole mount immunofluorescence staining and histological analysis showed a distribution of stem cells in the central/intermediate zones of spheroids. QRT-PCR analysis demonstrated that the expression of stemness markers NANOG, TP63 and CD44 in the spheroids were much higher than within the monolayer cultures. Gene expression levels of neural markers CDH2, NFM, TUBB3 and CD24 in the spheroids were much higher than the monolayer DPCs and increased in a culture time-dependent manner. Without any neural induction, spheroid-derived cells spontaneously converted into neuron-like cells with positive staining of neural markers HuC/D and P75 under the serum-free medium for about 2 weeks. When the spheroids were transferred into osteogenic medium, they rapidly differentiated into osteo/odontogenic cells, especially the central original cells. Compared to the monolayer DPCs, mineralization in spheroids were significantly increased. This spheroid model offers a study tool to explore the molecular bases of stem cell homeostasis and tissue organization, and can be wildly used for nerve tissue and bone regeneration. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · Jun 2013 · Journal of Cellular Biochemistry
Show more

We use cookies to give you the best possible experience on ResearchGate. Read our cookies policy to learn more.