Quantitative single cell biology of neural stem cells and cellular diversity
The cellular diversity of the human brain is immense, which is generated through evolutionarily conserved developmental mechanisms. The system is robust enough to create functional masterpiece; yet is susceptible to failure that may lead to cognitive dysfunction.
We study the molecular and cellular mechanisms underlying the functional diversity of the adult reward system, cell fate choices leading to its development and how these are affected in autism spectrum disorder. For this, we use state-of-the art single cell RNA/epigenome sequencing techniques, CRISPR-mediated gene inactivation, mouse genetics, bioengineered organoids and computational tools to run multidisciplinary, collaborative projects
The ventral tegmental area (VTA) is part of the reward system and is characterised as having a heterogeneous cell population that are organized in neural populations that exhibit a more gradual transition, making it difficult to define VTA borders. Extensive research has been done on the VTA, however not on a single cell level. As part of the BRAINSCAPES consortium, we are using single cell RNA-sequencing/ChIC-sequencing to generate reference atlases of the diverse cell populations within the VTA.
Our project will provide a new resource whose quality, precision and depth exceeds current literature. This data can be reused by researchers analysing traits linked to different mental disorders, such as depression, as well as those working on neurodegenerative disorders that affect the dopaminergic system, such as Parkinson’s Disease.
We also aim to determine how histone methylation contributes to the cellular heterogeneity in the adult brain and determine if long term histone modifications play a role in eating and stress disorders.
The cellular diversity of the reward system is just being discovered. Its developmental origins is yet to be fully understood. Determining the origins of this diversity may help us better understand how our brain is build, as well as whether the underlying molecular program is affected in neurodevelopmental disorders.
We aim to delineate the molecular and cellular mechanisms behind epigenetic regulation of cell fate decisions of neural stem cells (NSCs) during the development of the reward system. For this, we use mouse genetics, bioengineered and pattern organoids, CRISPR-mediate gene ablation and computational tools.
The reward system is defective in several psychiatric and neurodevelopmental disorders. Neurogenetics have identified thousands of risk alleles in hundreds of genes that are altered in patients of neurodevelopmental/psychiatric disorders. A missing link is the identification of how such a large number of mutations lead to diseases with similar sympthoms. A working hypothesis is respective fields is that specific cell types are affected in patients with different mutations. Recent advances in single cell genomics and computational biology offer tools to test these questions in silico. In addition, the boom of CRISPR-mediated gene editing and induced pluripotent stem cell derived neural organoid modelling provide the experimental tools to dissect the function of these mutations.
We have a special interest in understand how this hub of reward and social interaction is altered upon mutations associated with autism spectrum disorder (ASD). We use in utero electroporation assisted CRISPR-mediated gene editing, bioengineered and pattern organoids, to test the data-driven hypothesis.
Our group is part of the Utrecht Bioinformatics Center that performs Life Science research using big data analysis on DNA, genes, proteins and cells.. For more information please visit https://ubc.uu.nl/user/obasak/
You can access our lab webpage through here
Dr. Onur Basak
A coffee loving molecular biologist pretending to be a computational scientist, and leader of my pack!
Generating a single cell RNAseq/ChIC-seq reference atlas of the adult mouse VTA as part of the BRAINSCAPES consortium and determining how histone methylation contributes to the cellular heterogeneity and long term differences in perturbation within the reward system.
Single-cell omics, immunohistochemistry, Ventral Tegmental Area (VTA), cell/nuclei isolation from mouse brain.
Elucidating the developmental defects in Rett Syndrome using bioengineered organoid systems.
Bioengineering, immunohistochemistry, organoids, microfluidics
- Kakava-Georgiadou N, Drkelic V, Garner KM, Luijendijk MCM, Basak O, Adan RAH. Molecular profile and response to energy deficit of leptin-receptor neurons in the lateral hypothalamus. Sci Rep. 2022 Aug 4;12(1):13374. doi: 10.1038/s41598-022-16492-w. PMID: 35927440; PMCID: PMC9352899
- van de Haar LL, Riga D, Boer JE, Garritsen O, Adolfs Y, Sieburgh TE, van Dijk RE, Watanabe K, van Kronenburg NCH, Broekhoven MH, Posthuma D, Meye FJ, Basak O, Pasterkamp RJ. Molecular signatures and cellular diversity during mouse habenula development. Cell Rep. 2022 Jul 5;40(1):111029. doi: 10.1016/j.celrep.2022.111029. Epub 2016 Dec 8. PMID: 35793630
- Schneider J, Weigel J, Wittmann MT, Svehla P, Ehrt S, Zheng F, Elmzzahi T, Karpf J, Paniagua-Herranz L, Basak O, Ekici A, Reis A, Alzheimer C, Ortega de la O F, Liebscher S, Beckervordersandforth R. Astrogenesis in the murine dentate gyrus is a life-long and dynamic process. EMBO J. 2022 Jun 1;41(11):e110409. doi: 10.15252/embj.2021110409. Epub 2022 Apr 22. PMID: 35451150
- Stenudd M, Sabelström H, Llorens-Bobadilla E, Zamboni M, Blom H, Brismar H, Zhang S, Basak O, Clevers H, Göritz C, Barnabé-Heider F, Frisén J. Identification of a discrete subpopulation of spinal cord ependymal cells with neural stem cell properties. Cell Rep. 2022 Mar 1;38(9):110440. doi: 10.1016/j.celrep.2022.110440. PMID: 35235796
- Donega V, van der Geest AT, Sluijs JA, van Dijk RE, Wang CC, Basak O, Pasterkamp RJ, Hol EM. Single-cell profiling of human subventricular zone progenitors identifies SFRP1 as a target to re-activate progenitors. Nat Commun. 2022 Feb 24;13(1):1036. doi: 10.1038/s41467-022-28626-9. PMID: 35210419; PMCID: PMC8873234
- Donega V, Burm SM, van Strien ME, van Bodegraven EJ, Paliukhovich I, Geut H, van de Berg WDJ, Li KW, Smit AB, Basak O, Hol EM. Transcriptome and proteome profiling of neural stem cells from the human subventricular zone in Parkinson’s disease. Acta Neuropathol Commun. 2019 Jun 3;7(1):84. doi: 10.1186/s40478-019-0736-0. Erratum in: Acta Neuropathol Commun. 2019 Aug 14;7(1):131. PMID: 31159890; PMCID: PMC6545684
- Basak O, Krieger TG, Muraro MJ, Wiebrands K, Stange DE, Frias-Aldeguer J, Rivron NC, van de Wetering M, van Es JH, van Oudenaarden A, Simons BD, Clevers H. Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy. Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E610-E619. doi: 10.1073/pnas.1715911114. Epub 2018 Jan 8. PMID: 29311336; PMCID: PMC5789932