Investigation of the molecular mechanisms restricting the neurogenic potential of astrocytes

• Applicant: Dr. Michael Lattke
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2017 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 335078658

The inability of the central nervous system (CNS) to replace neurons lost in injury or neurodegeneration is a major problem in clinical medicine. Encouragingly, recent studies have shown that astrocytes, a major glial cell population in the CNS, can de-differentiate to a neural stem cell-like state and generate neurons in response to injury. However, this neurogenic response is spatially and quantitatively very limited, and the molecular mechanisms restricting this neurogenic potential are not understood. The identification of regulators that suppress the neurogenic potential of astrocytes might help to enhance their neurogenic responses to promote endogenous neuronal replacement, a potential strategy for regenerative medicine. In a re-analysis of a published gene expression dataset, transcription factors have been identified that are specifically upregulated during astrocyte maturation and might contribute to the restriction of the neurogenic potential of astrocytes.The main objectives of the proposed project are: (A) To assess the role of previously identified transcriptional regulators induced during astrocyte maturation in the restriction of the neurogenic potential of astrocytes. (B) To identify novel candidate regulators restricting the neurogenic potential of astrocytes. The function of the already identified transcription factors will be characterised by overexpression in neural stem cells in vitro, which will then be differentiated into astrocytes. The capacity of these cells to de-differentiate and generate neurons will be assessed. Transcriptional profiling will provide additional insights of the contribution of the regulators to astrocyte maturation. Previous studies suggest that Klf15, one of the candidates, is able to suppress neurogenesis and promote astrocyte differentiation. Therefore the function of Klf15 in the regulation of the neurogenic potential of astrocytes will also be assessed in vivo, in a loss-of-function mouse model, both in normal conditions and in genetically induced neurogenesis of striatal astrocytes.To allow a more detailed investigation of the molecular mechanisms that underlie the loss of the neurogenic potential of mature astrocytes, the project aims to improve existing differentiation protocols, to generate more mature astrocytes in vitro than is currently possible. Transcriptional changes at different stages of astrocyte differentiation will be analysed in vitro, to resolve this process in more detail and to identify additional repressors of the neurogenic potential of astrocytes.These in vitro and in vivo approaches will contribute to a better understanding of the neurogenic responses of astrocytes and their differentiation. They will also generate a basis for future studies that address the function of the identified regulators in greater depth. Finally, manipulation of these regulators may in the future allow stimulating endogenous neuronal replacement as an approach for regenerative medicine.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor Dr. Francois Guillemot