Project number 10

Unraveling astrocyte heterogeneity in the mouse brain using single cell transcriptome profiling

Astrocytes are the major cell type in mammalian brain. They perform many functions at both synapses and the blood brain barrier. Importantly, all major neurological disorders, such as Alzheimer’s disease and cancer, show astrocyte involvement.
Astrocytes have traditionally been studied as a homogeneous set of cells. However, recent reports suggest they are actually a highly heterogeneous cell population, showing variation in morphology, physiology and function. This raises the question of whether astrocytes are specialized to perform specific functions in defined regions of the CNS – and the implications for CNS disease.
We study astrocyte heterogeneity using transcriptomics. Applying single cell methods, we found that astrocytes are more heterogeneous than previously thought (with 8 subtypes in the adult mouse hippocampus).
We now wish to appoint a highly motivated student, who will work at the interface of both labs. The student will split their time 50:50 between the Holt  group (wet lab experiments) and Saeys group (single cell bioinformatics and systems biology methodologies), with the overall goal of elucidating how astrocyte subtypes develop and are maintained in the adult mouse CNS, as well as the functional consequences.
We will study astrocyte development by isolating single cells at closely related time points. Using single cell sequencing, the developmental relationship between cells will be established using trajectory inference methods. Emphasis will be on the identification of transcription factor networks driving subtype development.
Based on the bioinformatics, experiments manipulating transcription factor levels will be performed to force subtype interconversions. This will be followed by analysis of local tissue architecture (e.g. immunostainings and confocal microscopy for neuron number and density) and assays of CNS (subtype) function (electrophysiology and Ca2+ imaging).

astrocyte, transcriptomics, transcription factors, development, function

Yvan Saeys, VIB Inflammation Research Center, UGent, Gent
Matthew Holt, VIB Center for the Biology of Disease, KU Leuven, Leuven