We focus on the role of the cell nucleus in accelerated aging and age-related diseases, using high-dimensional microscopy and image informatics. Herebelow are the two major research topics we are currently working on, a list of past and present research projects can be found here.
Nuclear envelope stress in aging disease
The nuclear envelope (NE) serves as a central organizing unit for the eukaryotic cell. By virtue of its highly selective, semipermeable barrier function, the NE shields the enclosed genetic material, while ensuring its regulated transcription, replication, and repair. The NE has long been considered to only dismantle during mitosis. However, in recent years it has become clear that in a variety of pathologies such as laminopathies, cancer and viral infections, NE integrity becomes compromised during interphase as well (De Vos et al. 2011). We investigate the molecular mechanisms of NE stress in different disease settings by different means: to bypass scarcity and heterogeneity of patient material, we develop genome-edited model cell lines; to gain robust molecular readouts, we develop high-throughput cell imaging pipelines (Robijns et al. 2016); and to bypass the unpredictable nature of spontaneous ruptures, we establish optical/physical methods to perturb NE function in a targeted manner (Houthaeve et al. 2018)…
- W. De Vos, F. Houben, M. Kamps, J. Cox, P. Van Oostveldt, V. Verstraeten, M. van Steensel, C. Marcelis, A. van den Wijngaard, F. Ramaekers and J. Broers (2011). Repetitive Disruptions of the Nuclear Envelope Invoke Temporary Loss of Cellular Compartmentalization in Laminopathies. Human Molecular Genetics 20(21), p.4175-4186.
- J. Robijns, F. Molenberghs, T. Sieprath, T. Corne, M. Verschuuren and W. De Vos (2016). In silico synchronization reveals regulators of nuclear ruptures in lamin A/C deficient model cells. Scientific reports 6(30325), p. 1-11.
- G. Houthaeve, R. Xiong, J. Robijns, B. Luyckx, Y. Beulque, T. Brans, C. Campsteijn, S. Samal, S. Stremersch, S. De Smedt, K. Braeckmans and W. De Vos (2018). Targeted Perturbation of Nuclear Envelope Integrity with Vapor Nanobubble-Mediated Photoporation. ACS Nano 12 (8), p. 7791-7802.
Morphofunctional connectivity in neurodegeneration
Long-term adaptations of the brain, such as memory formation, rely on a delicate dialogue between neurons that is typified by intensive remodeling of both cellular and nuclear morphology. We are specifically interested in the alterations that take place during aging and neurodegenerative disorders. To this end, we have optimized a high-throughput microscopy pipeline for interrogating morphological and functional connectivity in primary neuronal cultures, using a combination of quantitative immunofluorescence and live cell calcium imaging, respectively (Verschuuren et al. 2019). The resulting morphofunctional readout allows accurate classification and prediction of the degree of connectivity or maturity of specific neuronal culture. We are now refining this approach to understand the relationship with nuclear structure and remodeling…
At a higher level, we have optimized a whole brain imaging approach based on tissue clearing and light sheet microscopy, with which we have staged tau pathology in a seeded mouse model (Detrez et al 2019). We thereby identified a unique microglial response, which we are now characterizing in more detail using a combination of molecular and microscopic approaches…
- M. Verschuuren, P. Verstraelen, G. García-Díaz Barriga, I. Cilissen, E. Coninx, M. Verslegers, P. Larsen, R. Nuydens, W. De Vos (2019). High-throughput microscopy exposes a pharmacological window in which dual leucine zipper kinase inhibition preserves neuronal network connectivity. Acta Neuropathologica Communications 7, 93.
- J. Detrez, H. Maurin, K. Van Kolen, R. Willems, J. Colombelli, B. Lechat, B. Roucourt, F. Van Leuven, S. Baatout, P. Larsen, R. Nuydens, J.-P. Timmermans, W. De Vos (2019). Regional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain. Neurobiology of Disease 127, p. 398-409