Lineage tracing of the human brain
This project aims to utilize somatic DNA variants to trace cell lineages in human brain development, revealing cellular processes and methodologies applicable to various tissues and pathologies.
Projectdetails
Introduction
Organisms develop through cell divisions generating clones that progressively organize to form different tissues. This process can be visualized as a cell phylogeny by lineage tracing. In order to track cell lineages, each cell division has to be permanently and uniquely marked.
Genome Editing in Model Systems
In model systems, this is done by genome editing. In humans, this is not applicable, which has historically made it impossible to accurately study cell phylogenies. Very recently, however, studies showed that human tissues contain a set of natural markers in the form of somatic DNA variants that permanently and cumulatively label every cell division during development.
Reliability of Somatic Variants
My work showed that somatic variants are reliable at tracking cell lineages directly in human tissues. Human brain development has historically been difficult to address since human-brain-specific features are hardly recapitulated in any existing model.
Project Overview
My project now builds on the use of somatic variants to reveal the cellular processes that form the brain starting from available human material. Somatic variants will be identified at unprecedented sensitivity in a large set of human fetal tissues, including multiple different brain regions.
Work Packages
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WP1: I will identify and study the lineage segregation steps defining the brain phylogeny starting from the zygote. Mathematical modelling will elucidate mechanisms of clone dynamics.
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WP2: I will focus on the cerebral cortex and reconstruct cell phylogenies of neural progenitors and the distribution of cortical clones. Furthermore, I will compare normal versus overgrowth cortical malformation brains, where cell proliferation and migration are altered.
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WP3: I will develop new strategies to simultaneously assess cell phylogenies and cell-type specification by identifying somatic variants in multi-omics data.
Conclusion
This project will reveal the unfolding of the cellular lineages building the human brain while providing a methodology that is applicable to any tissue and pathology.
Financiële details & Tijdlijn
Financiële details
Subsidiebedrag | € 1.800.000 |
Totale projectbegroting | € 1.800.000 |
Tijdlijn
Startdatum | 1-6-2024 |
Einddatum | 31-5-2029 |
Subsidiejaar | 2024 |
Partners & Locaties
Projectpartners
- INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALEpenvoerder
- IMAGINE INSTITUT DES MALADIES GENETIQUES NECKER ENFANTS MALADES FONDATION
- INSTITUT DU CERVEAU ET DE LA MOELLE EPINIERE
Land(en)
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