Investigating lamin B1-directed nuclear architecture in aging of adult hippocampal neurogenesis

• Applicant: Professor Dr. Tomohisa Toda, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 470322152

The goal of this proposal is to unravel the mechanism underlying the aging of adult neural stem/progenitor cells (ANSPCs) in the hippocampus. Maintaining ANSPCs is critical for adult brain plasticity, but ANSPCs decrease with aging. To prevent aging of ANSPCs or rejuvenate ANSPCs, we need to understand the underlying mechanisms of stem cell aging. Our group recently identified lamin B1 as a cell intrinsic driver of ANSPC’s aging. The levels of lamin B1 in ANSPCs decrease during aging, and the precocious reduction of lamin B1 impairs the maintenance of adult neurogenesis. However, how lamin B1 regulates aging of ANSPCs is still unclear. Thus, in the proposed project, we aim to address how and to what extent lamin B1-directed nuclear architecture underlies ANSPC’s epigenetic and transcriptomic regulation. We hypothesize that aging affects ANSPCs through the deterioration of laminB1-directed nuclear architecture. Nuclear architecture represents the characteristic distribution of heterochromatin/euchromatin and underlies cell type-specific gene regulation. Nuclear lamina regulates nuclear architecture through their interaction with heterochromatin. The objectives of experiments proposed here are i) to address age- and lamin B1-dependent changes in ANSPC specific nuclear architecture, ii) to investigate roles of lamin B1-directed nuclear architecture in epigenetic and transcriptomic changes in vivo, iii) to study how lamin B1-depletion affect the integration of newborn neurons and cognitive function. To address these points, we will use transgenic mouse models in combination with histological, deep sequencing and behavioral approaches. The successful completion of this research will uncover roles of lamin B1-directed nuclear architecture and epigenetic regulation on the maintenance of ANSPCs. These results will provide fundamental knowledge regarding neural stem cell aging and help to develop therapeutic strategies by restoring the plasticity potential of aged neural stem cells.

• DFG Programme: Research Grants