José Manuel Morante-Redolat

University of Valencia, Valenza, Valencia, Spain

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Publications (8)115.29 Total impact

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    ABSTRACT: The identification of mechanisms that maintain stem cell niche architecture and homeostasis is fundamental to our understanding of tissue renewal and repair. Cell adhesion is a well-characterized mechanism for developmental morphogenetic processes, but its contribution to the dynamic regulation of adult mammalian stem cell niches is still poorly defined. We show that N-cadherin-mediated anchorage of neural stem cells (NSCs) to ependymocytes in the adult murine subependymal zone modulates their quiescence. We further identify MT5-MMP as a membrane-type metalloproteinase responsible for the shedding of the N-cadherin ectodomain in this niche. MT5-MMP is co-expressed with N-cadherin in adult NSCs and ependymocytes and, whereas MT5-MMP-mediated cleavage of N-cadherin is dispensable for the regulation of NSC generation and identity, it is required for proper activation of NSCs under physiological and regenerative conditions. Our results indicate that the proliferative status of stem cells can be dynamically modulated by regulated cleavage of cell adhesion molecules.
    Nature Cell Biology 06/2014; · 20.06 Impact Factor
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    ABSTRACT: Relative quiescence and self renewal are defining features of adult stem cells, but their potential coordination remains unclear. Subependymal neural stem cells (NSCs) lacking cyclin-dependent kinase (CDK) inhibitor (CKI) 1a (p21) exhibit rapid expansion that is followed by their permanent loss later in life. Here we demonstrate that transcription of the gene encoding bone morphogenetic protein 2 (Bmp2) in NSCs is under the direct negative control of p21 through actions that are independent of CDK. Loss of p21 in NSCs results in increased levels of secreted BMP2, which induce premature terminal differentiation of multipotent NSCs into mature non-neurogenic astrocytes in an autocrine and/or paracrine manner. We also show that the cell-nonautonomous p21-null phenotype is modulated by the Noggin-rich environment of the subependymal niche. The dual function that we describe here provides a physiological example of combined cell-autonomous and cell-nonautonomous functions of p21 with implications in self renewal, linking the relative quiescence of adult stem cells to their longevity and potentiality.
    Nature Neuroscience 10/2013; · 14.98 Impact Factor
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    ABSTRACT: The gene for the atypical NOTCH ligand delta-like homologue 1 (Dlk1) encodes membrane-bound and secreted isoforms that function in several developmental processes in vitro and in vivo. Dlk1, a member of a cluster of imprinted genes, is expressed from the paternally inherited chromosome. Here we show that mice that are deficient in Dlk1 have defects in postnatal neurogenesis in the subventricular zone: a developmental continuum that results in depletion of mature neurons in the olfactory bulb. We show that DLK1 is secreted by niche astrocytes, whereas its membrane-bound isoform is present in neural stem cells (NSCs) and is required for the inductive effect of secreted DLK1 on self-renewal. Notably, we find that there is a requirement for Dlk1 to be expressed from both maternally and paternally inherited chromosomes. Selective absence of Dlk1 imprinting in both NSCs and niche astrocytes is associated with postnatal acquisition of DNA methylation at the germ-line-derived imprinting control region. The results emphasize molecular relationships between NSCs and the niche astrocyte cells of the microenvironment, identifying a signalling system encoded by a single gene that functions coordinately in both cell types. The modulation of genomic imprinting in a stem-cell environment adds a new level of epigenetic regulation to the establishment and maintenance of the niche, raising wider questions about the adaptability, function and evolution of imprinting in specific developmental contexts.
    Nature 07/2011; 475(7356):381-5. · 42.35 Impact Factor
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    ABSTRACT: Mutations in leucine-rich glioma inactivated (LGI1) are a genetic cause of autosomal dominant temporal lobe epilepsy with auditory features. LGI1 is a secreted protein that shares homology with members of the SLIT family, ligands that direct axonal repulsion and growth cone collapse, and we therefore considered the possibility that LGI1 may regulate neuronal process extension or growth cone collapse. Here we report that LGI1 does not affect growth directly but instead enhances neuronal growth on myelin-based inhibitory substrates and antagonizes myelin-induced growth cone collapse. We show that LGI1 mediates this effect by functioning as a specific Nogo receptor 1 (NgR1) ligand that antagonizes the action of myelin-based inhibitory cues. Finally, we demonstrate that NgR1 and ADAM22 physically associate to form a receptor complex in which NgR1 facilitates LGI1 binding to ADAM22.
    Journal of Neuroscience 05/2010; 30(19):6607-12. · 6.75 Impact Factor
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    Celia Andreu-Agulló, José Manuel Morante-Redolat, Ana C Delgado, Isabel Fariñas
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    ABSTRACT: We sought to address the fundamental question of how stem cell microenvironments can regulate self-renewal. We found that Notch was active in astroglia-like neural stem cells (NSCs), but not in transit-amplifying progenitors of the murine subependymal zone, and that the level of Notch transcriptional activity correlated with self-renewal and multipotency. Moreover, dividing NSCs appeared to balance renewal with commitment via controlled segregation of Notch activity, leading to biased expression of known (Hes1) and previously unknown (Egfr) Notch target genes in daughter cells. Pigment epithelium-derived factor (PEDF) enhanced Notch-dependent transcription in cells with low Notch signaling, thereby subverting the output of an asymmetrical division to the production of two highly self-renewing cells. Mechanistically, PEDF induced a non-canonical activation of the NF-kappaB pathway, leading to the dismissal of the transcriptional co-repressor N-CoR from specific Notch-responsive promoters. Our data provide a basis for stemness regulation in vascular niches and indicate that Notch and PEDF cooperate to regulate self-renewal.
    Nature Neuroscience 11/2009; 12(12):1514-23. · 14.98 Impact Factor
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    ABSTRACT: The leucine-rich glioma inactivated (LGI) gene subfamily contains four highly conserved members (LGI1, 2, 3 and 4), which have been described in human, mouse and other mammalians. Although their main roles remain unknown, LGI1 gene mutations have been found in human partial temporal lobe epilepsy. Moreover, previous studies showed that the products of these genes exert their function in the nervous system. The anatomical distribution of these gene transcripts in the brain might give some insight to elucidate their possible function. In this study, the pattern of expression of the four LGI genes was assessed in the brain of C57BL/6J adult mice by in situ hybridization. We found that the LGI1 transcript is mainly expressed in the dentate gyrus and CA3 field of the hippocampus. LGI2 and LGI4 genes, which showed a similar pattern of distribution with minor differences, were mostly expressed in the medial septal area, thalamic reticular nucleus and substantia nigra pars compacta. LGI3-expressing cells were distributed widespread, but were more consistently observed in the hippocampal formation, thalamic and hypothalamic nuclei, substantia nigra and reticular formation. In summary, LGI1 gene expression is very restricted to intrahippocampal circuitry, which might be related to its involvement in temporal lobe epilepsy. The patterns of expression of LGI2 and LGI4 genes are very similar and their distribution in the vertical limb of the diagonal band and in putative hippocampal interneurons suggests that the function of these genes might be related to the generation of hippocampal theta rhythm. Finally, LGI3 gene widespread expression in the brain suggests that its transcripts might be involved in a common cellular process present in different neuronal types.
    Brain research 10/2009; 1307:177-94. · 2.83 Impact Factor
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    ABSTRACT: Autosomal dominant lateral temporal epilepsy (ADTLE) is a partial epilepsy caused by mutations in LGI1, a multidomain protein of unknown function. To begin to understand the biological function of LGI1, we have determined its pattern of glycosylation, subcellular expression and capacity for secretion. LGI1 is expressed as two different isoforms in the brain, and we show that the long isoform is a secreted protein, whereas the short isoform is retained in an intracellular pool. ADLTE-related mutants of the long form are defective for secretion and are retained in the endoplasmic reticulum and Golgi complex. Finally, we show that normal secreted LGI1 specifically binds to the cell surface of differentiated PC12 cells. We propose that LGI1 is a secreted factor important for neuronal development and that ADTLE is a disease that results from the loss of regulation in the protein available either extracellular or intracellularly.
    Human Molecular Genetics 01/2007; 15(23):3436-45. · 6.68 Impact Factor
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    ABSTRACT: Autosomal dominant lateral temporal epilepsy (EPT; OMIM 600512) is a form of epilepsy characterized by partial seizures, usually preceded by auditory signs. The gene for this disorder has been mapped by linkage studies to chromosomal region 10q24. Here we show that mutations in the LGI1 gene segregate with EPT in two families affected by this disorder. Both mutations introduce premature stop codons and thus prevent the production of the full-length protein from the affected allele. By immunohistochemical studies, we demonstrate that the LGI1 protein, which contains several leucine-rich repeats, is expressed ubiquitously in the neuronal cell compartment of the brain. Moreover, we provide evidence for genetic heterogeneity within this disorder, since several other families with a phenotype consistent with this type of epilepsy lack mutations in the LGI1 gene.
    Human Molecular Genetics 06/2002; 11(9):1119-28. · 6.68 Impact Factor

Publication Stats

353 Citations
115.29 Total Impact Points


  • 2009–2013
    • University of Valencia
      • Cellular Biology and Parasitology
      Valenza, Valencia, Spain
  • 2011
    • Centro de Investigación Biomédica en Red, Enfermedades Neurodegenerativas
      Madrid, Madrid, Spain