Molecular and cellular neurobiotechnology

Prof. Dr. del Río, José Antonio
Group Leader


Edifici Hèlix | Baldiri Reixac, 15-21 | 08028 | Barcelona
Email : jadelrioibecbarcelona.eu

Research Topics

Atomic force microscopy / Microarrays analysis / Gene cloning and expression of developmentally regulated genes / Pharmacological treatments to promote axon regeneration / Prion biology / Neurodegenerative diseases / Neural stem cells

During 2012, the research group has developed several studies aimed at understanding some processes of development and neurodegeneration of the central nervous system (CNS).

Role of PrPc in the nervous system. We have demonstrated, in collaboration with other groups, the role of the cellular prion protein (PrPc) in neural stem cell proliferation and differentiation, in particular oligodendrocyte precursor cells (OPCs). Our data indicate that PrPc influences oligodendrocyte proliferation in the developing and adult CNS. OPCs that lack PrPc proliferate more vigorously at the expense of a delay in differentiation, which correlates with changes in the expression of oligodendrocyte lineage markers. In addition, numerous NG2-positive cells were observed in cortical regions of adult PrPc knockout mice, although no significant changes in myelination can be seen, probably due to the death of surplus cells (Bribian et al., 2012)

In addition, our data indicate that PrPc also modulate glutamatergic neutransmission by acting at the cell membrane together with the glutamate receptor subunits Glur6/7 and the postsynaptic density protein PSD-95. Thus the absence of PrPc induces epilepsy by lacking the interaction with the glutamate receptor. In addition, we demonstrated that an intracellular kinase JNK3 is a target of PrPc mediated signaling. These data have been included in a perspectives report in Prion (Llorens & Del Río, 2012).

Example of LEICA SP5 spinning disk confocal microscopy picture showing one example of hippocampus in the new mouse Cre/lox models generated by the group. In the example, labeled axons of CAMKII positive cells are labeled in yellow or green after recombination and fluorochrome switch.

NeuroMEMs. New platforms for neural culture and analysis. From the technological point of view, the group published a methodological review in Nature Protocols on the usefulness of three-dimensional culture with hydrogels in neurobiological studies. The method is easy and is generally reproducible and only few specific details can be taken into account during its development. The degree and behavior of axonal growth or neural migration can be seen directly by using eGFP transgenic mice as a source of neural tissue or by immunostaining (Gil & Del Río, 2012).

Regenerative neuroscience. Moreover, in collaboration with other IBEC groups, we have characterized the role of myelin-associated proteins and its intracellular signaling cascades in the development of cell therapies using olfactory ensheathing cells. These cells are inhibited by myelin. In collaboration with Xavier Trepat’s group we have determined for the first time the behavior of these cells using biomechanics and traction force analysis (Nocentini et al., 2012). Current experiments of our groups are directed to avoid this inhibition in order to increase the effectiveness of this cell type after spinal cord lesion.

Finally, group members have collaborated on the study of the analysis of Neuregulin-1/Erb4 signaling in OPCs migration (Ortega et al., 2012) as well the role of the Semaphorin 4F during its maturation (Armendariz et al., 2012).

Example of LEICA SP5 spinning disk confocal microscopy picture showing Cajal-Retzius cells (green) migrating in a hydrogel 3D culture.

Current experiments. Current experiments are directed to develop optogenetic non-invasive bioessays to analyze neuronal migration during brain development. In this collaboration with Ángel Raya’s group we have generated transgenic mice with the expression of switchable fluorochromes under specific promoters to label particular neural populations. In particular the migration of pioneer neurons, Cajal-Retzius cells, is already being analyzed using these transgenic mice.

• Prof. Dr. José Antonio del Río | Group Leader
• Dr. Rosalina Gavín | Postdoctoral Researcher
• Dr. Vanessa Gil | Postdoctoral Researcher
• Dr. Franc Llorens | Postdoctoral Researcher
• Patricia Carulla | PhD Student
• Sara Nocentini | PhD Student
• Diego Reginensi | PhD Student
• Oscar Seira | PhD Student
• Cristina Vergara | PhD Student
• Agata Mata | Master Student
• Andreu Matamoros | Undergraduate Student

• Medina-Rodriguez, E., Arenzana, F., Pastor, J., Redondo, M., Palomo, V., Garcia de Sola, R., Gil, C., Martinez, A., Bribian, A. & de Castro, F. (2013). Inhibition of endogenous phosphodiesterase 7 promotes oligodendrocyte precursor differentiation and survival. Cell Mol Life Sci., in press.
• La Torre, A., Del Mar Masdeu, M., Cotrufo, T., S., M. R., del Río, J. A., Comella, J., Soriano, E. & Ureña, J. (2013). A role for the tyrosine kinase ACK1 in neurotrophin signaling and neuronal extension and branching. Cell Death Dis., 18(4), e602.
• Llorens, F., Carulla, P., Villa, A., Torres, J., Fortes, P., Ferrer, I. & del Río, J. A. (2013). PrPC regulates EGFR function and cell shape dynamics in Neuro2a cells. J Neurochemistry, in press.
• Llorens, F., Bañez-Coronel, M., Pantano, L., del Río, J. A., Ferrer, I., Estivill, X. & Martí, E. (2013). A highly expressed miR-101 isomiR is a functional silencing small RNA. BMC Genomics, 14(104).
• Gil, V. & del Río, J. A. (2012). Analysis of axonal growth and cell migration in 3D hydrogel cultures of embryonic mouse CNS tissue. Nature Protocols, 7(2), 268–280.
• Nocentini, S., Reginensi, D., García, S., Carulla, P., Moreno-Flores, M., Wandosell, F., Trepat, X., Bribian, A. & del Río, J. A. (2012). Myelin-associated proteins block the migration of olfactory ensheathing cells: an in vitro study using single-cell tracking and traction force microscopy. Cell Mol Life Sci, in press, 69(10), 1689-703.
• Armendariz, B., Bribian, A., Perez-Martinez, E., Martinez, A., de Castro, F., Soriano, E. & Burgaya, F. (2012). Expression of Semaphorin 4F in neurons and brain oligodendrocytes and the regulation of oligodendrocyte precursor migration in the optic nerve. Mol Cell Neurosci., 49(1), 54-67.
• Llorens, F. & del Río, J. A. (2012). Unraveling the neuroprotective mechanisms of PrPC in excitotoxicity. Prion, 6(3), 1-7.
• Bribian, A., Fontana, X., Llorens, F., Gavín, R., Reina, M., García-Verdugo, J. M., Torres, J. M., de Castro, F. & del Río, J. A. (2012). Role of the Cellular Prion Protein in Oligodendrocyte Precursor Cell Proliferation and Differentiation in the Developing and Adult Mouse CNS. PLoS One, 2012;7(4):e33872.
• Ortega, M. C., Bribian, A., Peregrín, S., Gil, M. T., Marín, O. & de Castro, F. (2012). Neuregulin-1/ErbB4 signaling controls the migration of oligodendrocyte precursor cells during development. Experimental Neurology, 235(2), 610-620.
• Llorens, F., Gil, V. & del Río, J. A. (2011). Emerging functions of myelin-associated proteins during development, neuronal plasticity, and neurodegeneration. FASEB J, 25(2), 463-75.
• Carulla, P., Bribian, A., Rangel, A., Gavín, R., Ferrer, I., Caelles, C., del Río, J. A. & Llorens, F. (2011). Neuroprotective role of PrPC against Kainate-induced epileptic seizures and cell death depends on the modulation of JNK3 activation by GluR6/7-PSD-95 binding. Mol Biol Cell, 22, 3041-3054.
• Llorens, F., Hummel, M., Pastor, X., Ferrer, A., Pluvinet, R., Vivancos, A., Castillo, E., Iraola, S., Mosquera, A., Gonzalez, E., Lozano, J., Ingham, M., Dohm, J., Noguera, M., Kofler, R., del Río, J. A., Bayes, M., Himmelbauer, H. & Sumoy, L. (2011). Multiple platform assessment of the EGF dependent transcriptome by microarray and deep tag sequencing analysis. BMC Genomics, 12(1), 326.
• Marti, E., Pantano, L., Bañez-Coronel, M., Llorens, F., Miñones-Moyano, M., Porta, S., Sumoy, L., Ferrer, I. & Estivill, X. (2010). A myriad of miRNA variants in control and Huntington’s disease brain regions detected by massively parallel sequencing. Nucl. Acids Res., 38(20), 7219-7235.
• Vitureira, N., Andres, R., Perez-Martinez, E., Martinez, A., Bribian, A., Blasi, J., Chelliah, S., Lopez-Domenech, G., De Castro, F., Burgaya, F., McNagny, K. & Soriano, E. (2010). Podocalyxin is a novel polysialylated neural adhesion protein with multiple roles in neural development and synapse formation. PLoS One, 8(5), e12003.
• Madroñal, A., López-Aracil, C., Rangel, A., del Río, J. A., Delgado-García, J. M. & Gruart, A. (2010). Effects of Enriched Physical and Social Environments on Motor Performance, Associative Learning, and Hippocampal Neurogenesis in Mice. PLoS ONE, 5(6), e11130.
• Messeguer, J., Masip, I., Montolio, M., del Río, J. A., Soriano, E. & Messeguer, A. (2010). Peptoids bearing tertiary amino residues in the n-alkyl side chains: synthesis of a potent inhibitor of Semaphorin 3A. Tetrahedron, 66(13), 2444-2454.
• del Río, J. A. & Soriano, E. (2010). Regenerating cortical connections in a dish: the entorhino-hippocampal organotypic slice co-culture as tool for pharmacological screening of molecules promoting axon regeneration. Nat Protoc, 5(2), 217-26.
• Seira, O., Gavín, R., Gil, V., Llorens, F., Rangel, A., Soriano, E. & del Río, J. A. (2010). Neurites regrowth of cortical neurons by GSK3β inhibition independently of Nogo receptor 1. J Neurochem, 113(6), 1644-58.
• Gil, V., Bichler, Z., Lee, J. K., Seira, O., Llorens, F., Bribian, A., Morales, R., Claverol-Tinturé, E., Soriano, E., Sumoy, L., Zheng, B. & del Río, J. A. (2010). Developmental Expression of the Oligodendrocyte Myelin Glycoprotein in the Mouse Telencephalon. Cerebral Cortex, 20(8), 1769-1779.
• Montolio, M., Messeguer, J., Masip, I., Guijarro, P., Gavín, R., del Río, J. A., Messeguer, A. & Soriano, E. (2009). A semaphorin 3A inhibitor blocks axonal chemorepulsion and enhances axon regeneration. Chemistry & Biology, 16(7), 691-701.
• Nicolas, O., Gavín, R. & del Río, J. A. (2009). New insights into cellular prion protein (PrPc) functions: the "ying and yang" of a relevant protein. Brain Research Reviews, 61(2), 170-184.
• Aguado, F., Diaz-Ruiz, C., Parlato, R., Martinez, A., Carmona, M. A., Bleckmann, S., Urena, J. M., Burgaya, F., del Río, J. A., Schutz, G. & Soriano, E. (2009). The CREB/CREM Transcription Factors Negatively Regulate Early Synaptogenesis and Spontaneous Network Activity. J. Neurosci., 29(2), 328-333.
• Gavín, R., Ferrer, I. & del Río, J. A. (2009). Involvement of Dab1 in APP processing and B-amyloid deposition in sporadic Creutzfeldt-Jakob patients. Neurobiology of Disease, 37(2), 324-329.
• Rangel, A., Madroñal, N., Massó, ., Gavín, R. & Llorens, F. (2009). Regulation of GABAA and Glutamate Receptor Expression, Synaptic Facilitation and Long-Term Potentiation in the Hippocampus of Prion Mutant Mice. PLoS ONE, 4(10), e7592.
• Morales, R., Riss, M., Wang, L., Gavín, R., del Río, J. A., Alcubilla, R. & Claverol-Tinturé, E. (2008). Integrating multi-unit electrophysiology and plastic culture dishes for network neuroscience. Lab Chip, 8, 1896-1905.
• Gavín, R., Ureña, J., Rangel, A., Pastrana, M. A., Requena, J. R., Soriano, E., Aguzzi, A. & del Río, J. A. (2008). Fibrillar prion peptide PrP(106-126) treatment induces Dab1 phosphorylation and impairs APP processing and A[beta] production in cortical neurons. Neurobiology of Disease, 30(2), 243 - 254.
• Bribian, A., Esteban, P. F., Clemente, D., Soussi-Yanicostas, N., Thomas, J.-L., Zalc, B. & de Castro, F. (2008). A novel role for anosmin-1 in the adhesion and migration of oligodendrocyte precursors. Developmental Neurobiology, 68(13), 1503-1516.
• Llorens, F., Gil, V., Iraola, S., Carim-Todd, L., Martí, E., Estivill, X., Soriano, E., del Río, J. A. & Sumoy, L. (2008). Developmental analysis of Lingo-1/Lern1 protein expression in the mouse brain: Interaction of its intracellular domain with Myt1l. Developmental Neurobiology, 68(4), 521-541.
• Nicolas, O., Gavín, R., Braun, N., Ureña, J. M., Fontana, X., Soriano, E., Aguzzi, A. & del Río, J. A. (2007). Bcl-2 overexpression delays caspase-3 activation and rescues cerebellar degeneration in prion-deficient mice that overexpress amino-terminally truncated prion. The FASEB Journal, 21(12), 3107-3117.
• Meur, A. M., Zheng, B., Soriano, E. & del Río, J. A. (2007). Involvement of the Myelin-Associated Inhibitor Nogo-A in Early Cortical Development and Neuronal Maturation. Cerebral Cortex, 17(10), 2375-2386.
• del Río, J. A. & Soriano, E. (2007). Overcoming Chondroitin Sulphate Proteoglycan Inhibition of Axon Growth in the Injured Brain: Lessons from Chondroitinase ABC. Current Pharmaceutical Design, 13, 2485-2492(8).
• Merchán, P., Bribian, A., Sánchez-Camacho, C., Lezameta, M., Bovolenta, P. & de Castro, F. (2007). Sonic hedgehog promotes the migration and proliferation of optic nerve oligodendrocyte precursors. Molecular and Cellular Neuroscience, 36(3), 355 - 368.
• Soriano, E. & del Río, J. A. (2005). The cells of Cajal-Retzius: Still a mystery one century later. Neuron, 46(3), 389-394.
• Almendros, I., Montserrat, J. M., Torres, A., Bonsignore, M. R., Chimenti, L., Navajas, D. & Farré, R. Obesity and intermittent hypoxia increase tumor growth in a mouse model of sleep apnea. Sleep Medicine, 13(10), 1254-1260.

Projects

• BESAD-P: Biomarkers of early stages of Alzheimer's disease prevention CIBERNED intramural project. José Antonio Del Río
• PRIORITY: Protecting the food chain of prions: Shaping European priorities through basic and applied research EU - Cooperation - KBBE. José Antonio Del Río (third party)
  
• DEVREG: Caracterización funcional de genes regulados durante la ontogenia del SNC en el desarrollo cortical y la regeneración axonal (2009-2012) MICINN. José Antonio Del Río
• SGR2009: Grup de recerca consolidad de la Generalitat de Catalunya (2010-2014) AGAUR. José Antonio Del Río
  
• DEMTEST: Biomarker based diagnosis of rapid progressive dementias - optimisation of diagnostic protocols EU Joint Programme - Neurodegenerative Disease Research (JPND). José Antonio Del Río
• PRIONTAU: Papel de la proteína priónica celular en la fosforilación de tau en enfermedades neurodegenerativas

  FIS. Rosalina Gavín (managed by UB)

Collaborations

• Prof. Yutaka Yoshida Division of Developmental Biology, Cincinnati Children’s Research Foundation, Cincinnati, Ohio


• Prof. Fanny Man Developmental Institute of Marseille Luminy, Université de la Méditerranée, Marseille


• Angel Raya IBEC


• Xavier Trepat IBEC


• Dr. Jung Keun Hyun Dankook University, Yongin (Korea)


• Prof. Javier de Felipe Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid (Spain)


• Dr. Fernando de Castro Hospital Nacional de Parapléjicos, Toledo (Spain)


• Dr. Adolfo Lopéz de Munain Hospital de Donostia, San Sebastian (Spain)


• Prof. Jose Manuel García Verdugo Facultad de Ciencias, Universidad de Valencia (Spain)


• Prof. Josep A. Planell Institut de Bioenginyeria de Catalunya (IBEC)


• Prof. Josep Samitier Institut de Bioenginyeria de Catalunya (IBEC)


• Prof. Jesús Ávila and Prof. Francisco Wandosell Consejo Superior de Investigaciones Científicas (CSIC). Universidad Autónoma de Madrid


• Prof. Isidro Ferrer Institut d'Investigació Biomèdica de Bellvitge (IDIBELL). Universitat de Barcelona


• Prof. Marc Tessier Lavigne Genentech, Inc., South San Francisco, California, USA

• Neural stem cell culture
• Microscopy facility (Olympus BX61 and Olympus IX71 with LCi culture system)
• Electroporation system (BTX 600)
• Pressure microinjection system
• Protein expression and purification systems
• Technology of neuronal culture facilities (2D and 3D)
• Lentiviral production and characterization
• Gradient thermocycler (PCR)
• Protein and DNA electrophoresis
• In situ hybridization oven

14/03/2012

EU funding for research into Alzheimer’s and prioniopathies

A project involving IBEC through its affiliation with CIBERNED has been approved by the EU for funding.

02/01/2012

Shedding light on misbehaving cells

Much like a kindergarten full of unruly toddlers, the cells that contribute to the body’s crucial processes can’t always be trusted to do what you want or expect them to do. Now IBEC researchers have made an important breakthrough that could contribute to the development of therapies for spinal and neural diseases: they’ve figured out exactly what it is that makes certain cells misbehave in particular circumstances.

26/07/2011

'Identifying an essential interaction for epilepsy'

The Molecular and Cellular Neurotechnology group's recent paper on the development of epilepsy made the news today in Diario Medico, Spain’s leading newspaper for health professionals.

16/01/2011

'Beating the regeneration blockers' on the web

The 12 November press release about the Molecular and Cellular Neurobiotechnology group's research on inhibitory molecules in neuroregeneration, 'Beating the regeneration blockers', was picked up by various online scientific and health news sites including www.sciencedaily.com, the UK's MS Trust and Cell DNA.

12/11/2010

Beating the regeneration blockers

IBEC researchers shed light on inhibitory molecules in neuroregeneration

23/11/2009

Advances in neuronal regeneration

Prof. José Antonio del Río, leader of the Molecular and Cellular Neurobiotechnology research line at IBEC, has participated in a study on neural regeneration published in the journal Chemistry and Biology of the Cell group.