We focus on myelination, the process by which axons are invested with myelin, a lipid-rich biological membrane, which forms multilamellar, spirally wrapped sheets around axons. Myelination enables rapid saltatory conductance of action potentials and is essential for axonal integrity. The devastating neurological effects caused by the destruction of myelin in the central (CNS) and peripheral nervous system (PNS) illustrate well the importance of the process.
Schwann cells (SC) in the PNS and oligodendrocytes (OL) in the CNS proliferate and migrate before undergoing the remarkable morphological changes associated with ensheathing and myelination of axons. Precise control of these processes derives, at least in part, from instructive cues originating within the extracellular environment, in which proteins of the extracellular matrix (ECM) are essential components. Cell-ECM contact is largely mediated by integrins, a major group of ubiquitous cell-adhesion receptors for the proteins of the ECM.
Using conditional transgenic approaches in mice together with appropriate cell culture systems, we are investigating how integrin and rhoGTPases regulate the different stages of SC and OL development and myelination. By proteomics and next generation sequencing, we have identified novel candidate molecules regulating neuron-glial interactions that might also be relevant to enhance remyelination and repair. Their functions are currently being investigated.
More recently, we also became interested in integrin and rhoGTPases regulation of microglia function.
Over the last years, using conditional transgenic approaches, we have reported essential roles for integrin-linked-kinase, particularly interesting Cys-His-rich protein (PINCH), and for the RhoGTPases cdc42, rac1 and rhoA and some of their effectors, such as the actin binding protein profilin 1, in the regulation of different stages of SC and OL development and myelination. We have also reported roles for some of these molecules in neuroepithelium organization and neural progenitor differentiation. Group members have been funded by the FCT, ON2-QREN, Marie Curie actions (Laura Montani and Sofia Domingues), and EMBO long-term fellowships (Ligia Tavares). Research in the lab has been funded by the FCT, FP7, ETH Zurich, Swiss National Science Foundation and by the International Foundation for Paraplegia.
Evolvability of the actin cytoskeleton in oligodendrocytes during central nervous system development and aging. Cellular and Molecular Life Sciences76(1):, 2019. [Journal: Review] [CI: 10] [IF: 6,5]
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Azevedo M.M., Domingues H.S., Cordelières F.P., Sampaio P., Seixas A.I., Relvas J.B.,
Jmy regulates oligodendrocyte differentiation via modulation of actin cytoskeleton dynamics. GLIA66(9):1826-1844, 2018. [Journal: Article] [CI: 12] [IF: 5,8]
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Portugal C.C., Socodato R., Canedo T., Silva C.M., Martins T., Coreixas V.S.M., Loiola E.C., Gess B., Röhr D., Santiago A.R., Young P., Minshall R.D., Paes-De-Carvalho R., Ambrósio A.F., Relvas J.B.,
Caveolin-1-mediated internalization of the Vitamin C transporter SVCT2 in microglia triggers an inflammatory phenotype. Science Signaling10(472):, 2017. [Journal: Article] [CI: 36] [IF: 6,4]
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Socodato R., Portugal C.C., Domith I., Oliveira N.A., Coreixas V.S.M., Loiola E.C., Martins T., Santiago A.R., Paes-de-Carvalho R., Ambrósio A.F., Relvas J.B.,
c-Src function is necessary and sufficient for triggering microglial cell activation. GLIA63(3):497-511, 2015. [Journal: Article] [CI: 29] [IF: 6]
DOI: 10.1002/glia.22767 SCOPUS: 84920940260
Montani L., Buerki-Thurnherr T., de Faria J.P., Pereira J.A., Dias N.G., Fernandes R., Gonçalves A.F., Braun A., Benninger Y., Böttcher R.T., Costell M., Nave K.A., Franklin R.J.M., Meijer D., Suter U., Relvas J.B.,
Profilin 1 is required for peripheral nervous system myelination. Development141(7):1553-1561, 2014. [Journal: Article] [CI: 30] [IF: 6,5]
DOI: 10.1242/dev.101840 SCOPUS: 84896286838
Horn M., Baumann R., Pereira J.A., Sidiropoulos P.N.M., Somandin C., Welzl H., Stendel C., Lühmann T., Wessig C., Toyka K.V., Relvas J.B., Senderek J., Suter U.,
Myelin is dependent on the Charcot-Marie-Tooth Type 4H disease culprit protein FRABIN/FGD4 in Schwann cells. Brain135(12):3567-3583, 2012. [Journal: Article] [CI: 45] [IF: 9,9]
DOI: 10.1093/brain/aws275 SCOPUS: 84871796541
Herzog D., Loetscher P., van Hengel J., Knüsel S., Brakebusch C., Taylor V., Suter U., Relvas J.B.,
The small GTpase RhoA is required to maintain spinal cord neuroepithelium organization and the neural stem cell pool. Journal of Neuroscience31(13):5120-5130, 2011. [Journal: Article] [CI: 52] [IF: 7,1]
DOI: 10.1523/JNEUROSCI.4807-10.2011 SCOPUS: 79955713787
Pereira J.A., Benninger Y., Baumann R., Gonçalves A.F., Özçelik M., Thurnherr T., Tricaud N., Meijer D., Fässler R., Suter U., Relvas J.B.,
Integrin-linked kinase is required for radial sorting of axons and schwann cell remyelination in the peripheral nervous system. Journal of Cell Biology185(1):147-161, 2009. [Journal: Article] [CI: 89] [IF: 9,6]
DOI: 10.1083/jcb.200809008 SCOPUS: 65249163411
Benninger Y., Thurnherr T., Pereira J.A., Krause S., Wu X., Chrostek-Grashoff A., Herzog D., Nave K.A., Franklin R.J.M., Meijer D., Brakebusch C., Suter U., Relvas J.B.,
Essential and distinct roles for cdc42 and rac1 in the regulation of Schwann cell biology during peripheral nervous system development. Journal of Cell Biology177(6):1051-1061, 2007. [Journal: Article] [CI: 146] [IF: 9,6]
DOI: 10.1083/jcb.200610108 SCOPUS: 34250693117
Thurnherr T., Benninger Y., Wu X., Chrostek A., Krause S.M., Nave K.A., Franklin R.J.M., Brakebusch C., Suter U., Relvas J.B.,
Cdc42 and Rac1 signaling are both required for and act synergistically in the correct formation of myelin sheaths in the CNS. Journal of Neuroscience26(40):10110-10119, 2006. [Journal: Article] [CI: 98] [IF: 7,5]
DOI: 10.1523/JNEUROSCI.2158-06.2006 SCOPUS: 33749532141