Ivana Linenberg, Camila Pannunzio, Giuliana Di Mauro (co directed w/ Dr. Antonia Marin Burgin).
The neural circuits are constituted by a multiplicity of neurons that communicate through the release and action of neurotransmitters in interneuronal contacts called synapses. The human brain contains about 100 billion synapses. Far from being rigid structures, synapses are in constant structural and functional remodeling. These synaptic changes help explain, for instance, the processes of learning and memory. On the other hand, alterations in these processes of synaptic development, plasticity or remodeling can lead to different mental disorders, such as depression and anxiety, two psychiatric syndromes that our group have studied in detail.
Synapses are specialized junctions operated by highly complex protein-based molecular machineries whose composition and functional dynamics is tightly controlled by several post-translational modifications. Ubiquitin and Ubiquitin-like proteins (UBLs) like Sumo decisively control neuronal protein localization, interaction, turnover and activity, thereby regulating different aspects of dendritic and synaptic function. However, the role of other Ubiquitin-like proteins remains almost completely unknown.
Our group recently found that the UBL Nedd8, previously thought to exclusively influence cell proliferation, is the most highly expressed UBL in neurons and plays a fundamental role in synaptic development and stability. One of the main goals of the Molecular Neurobiology group is to elucidate the role of Nedd8 in neuronal development and function and its underlying molecular mechanisms, as well as its impact on cognitive and emotional behaviors.
Non-coding RNAs, including microRNAs, represent another central mechanism of post-transcriptional regulation of protein function and synthesis in dendritic and axonal microcompartments. Recently, our group has contributed to the identification and characterization of a new class of non-coding RNAs called circular RNAs (CircRNAs). These CircRNAs are highly expressed in the brain and enriched in synapses. However, its role in brain function and development in general and in synaptic activity in particular remains completely unexplored and is another aspect that our group tries to unravel.
Publications related to this project
- Szalai AM, Siarry B, Lukin J, Williamson DJ, Unsain N, Cáceres A, Pilo-Pais M, Acuna G, Refojo D, Owen DM, Simoncelli S, Stefani FD.
Three-dimensional total-internal reflection fluorescence nanoscopy with nanometric axial resolution by photometric localization of single molecules.
Nature Communications 12:517 (2021).
- Vogl AM, Phu L, Becerra R, Giusti SA, Verschueren E, Hinkle TB, Bordenave MD, Adrian M, Heidersbach A, Yankilevich P, Stefani FD, Wurst W, Hoogenraad CC, Kirkpatrick DS, Refojo D*, Sheng M*.
Global site-specific neddylation profiling reveals that NEDDylated cofilin regulates actin dynamics.
Nat Struct Mol Biol 27:210-220 (2020).
- Brockmann MM, Döngi M, Einsfelder U, Körber N, Refojo D, Stein V.
Neddylation regulates excitatory synaptic transmission and plasticity.
Sci Rep 9:17935 (2019)
- Dedic N, Kühne C, Jakovcevski M, Hartmann J, Genewsky A, Gomes KS, Anderzhanova E, Pöhlmann M, Chang S, Kolarz A, Vogl AM, Metzger MW, Schmid B, Almada RC, Ressler KJ, Wotjak CT, Grinevich V, Chen A, Schmidt MV, Wurst W, Refojo D, Deussing JM.
CRH acts anxiolytic by modulating dopamine release through a subset of GABAergic long-range projection neurons.
Nat Neurosci 21:803-807 (2018)
- Vogl AM, Brockmann MM, Giusti SA, Maccarrone G, Vercelli CA, Bauder CA, Richter JS, Roselli F, Hafner AS, Dedic N, Wotjak CT, Vogt-Weisenhorn DM, Choquet D, Turck CW, Stein V, Deussing JM, Refojo D.
Neddylation inhibition impairs spine development, destabilizes synapses and deteriorates cognition.
Nat Neurosci 18:239-51 (2015)
- Rybak-Wolf A., Stottmeister C., Glazar P., Jens M., Pino N., Giusti S., Hanan M., Behm M., Bartok O., Ashwal-Fluss R., Herzog M., Schreyer L., Papavasileiou P., Ivanov A., Öhman M., Refojo D., Kadener S., Rajewsky N.
Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed.
Molecular Cell 58, 1–16 (2015)
- Luxenhofer G, Helmbrecht MS, Langhoff J, Giusti S, Refojo D, Huber AB.
MicroRNA-9 promotes the switch from early-born to late-born motor neuron populations by regulating Onecut transcription factor expression.
Developmental Biology 386:358-70 (2014)
- Giusti SA, Vogl AM, Brockmann MM, Vercelli CA, Rein ML, Trümbach D, Wurst W, Cazalla D, Stein V, Deussing JM, Refojo D.
MicroRNA-9 controls dendritic development by targeting REST.
Elife 3 (2014)
- Refojo D, Schweizer M, Kuehne C, Ehrenberg S, Thoeringer C, Vogl AM, Dedic N, Schumacher M, von Wolff G, Avrabos C, Touma C, Engblom C, Schütz G, Nave K-A, Eder M, Wotjak CT, Sillaber I, Holsboer F, Wurst W, Deussing JM.
Glutamatergic and Dopaminergic Neurons Mediate Anxiogenic and Anxiolytic Effects of CRHR1.
Science 333:1903-1907 (2011)
- Lu A, Steiner MA, Whittle N, Vogl AM, Walser SM, Ableitner M, Refojo D, Ekker M, Rubenstein JL, Stalla GK, Singewald N, Holsboer F, Wotjak C, Wurst W, Deussing JM.
Conditional mouse mutants highlight mechanisms of corticotropin-releasing hormone effects on stress-coping behaviour.
Mol Psychiatry 13:1028-1042 (2008)
- Refojo, D., Echenique, C., Müller, M.B., Reul, J.M.H.M., Deussing, J.M., Wurst, W., Sillaber, I., Páez-Pereda, M., Holsboer, F., Arzt, E.
CRH activates ERK1/2 MAPK in specific brain areas.
PNAS – Proceedings of the National Academy of Sciences 102:6183-6188 (2005)