Mechanical signals are an important influence on the development, structure, and function of the central nervous system. Neural stem/progenitor cells (NSPCs), which generate neurons, astrocytes, and oligodendrocytes, are particularly sensitive to mechanical cues. During development, mechanical signals drive NSPC lineage specification, cell migration, and axon guidance. In stem cell transplant therapy, mechanical cues experienced by stem cells both in vitro before transplantation and in vivo after transplantation influence engraftment. Despite their manifest importance, the processes by which NSPCs detect, transduce, and generate mechanical forces remain poorly understood. Our overall objective is to uncover novel molecular mechanisms underlying NPSC mechano-regulation that could be harnessed for therapeutic strategies against neurodevelopmental and neurodegenerative diseases. We recently reported that the mechanically-activated ion channel Piezo1 generates Ca2+ flickers in NSPCs, and showed that its activity promotes differentiation into neurons rather than glia. Our new preliminary data also shows that Piezo1 knockout in mice results in gross abnormalities of the brain. Intriguingly, Piezo1 is active even in the absence of externally-applied mechanical force and this activity is triggered by cellular traction forces ? intracellular forces generated by the cell?s acto-myosin cytoskeleton to probe mechanical properties of the extracellular matrix. Here we examine the functional dynamics between traction forces and Piezo1 in NSPCs.
Aim 1 examines how traction forces activate Piezo1;
Aim 2 asks whether Piezo1 activity feeds back to modulate Myosin II activity;
and Aim 3 examines the role of the mechanical signaling between Piezo1 and Myosin II in neural tissue mechanics during development. These studies will provide a mechanistic insight into Piezo1?s role in regulating NSPC behavior in vitro and in vivo.
Neural stem/progenitor cells (NSPCs) are capable of generating the three main cell-types found in the brain - neurons, astrocytes and oligodendrocytes. They are critically important for building the brain during development and for neural repair therapies after injury or disease (e.g. spinal cord injury, Alzheimer?s disease, Parkinson?s disease etc.). The goal of this proposal is to understand the mechanisms by which mechanical signals encountered by NSPCs in vitro and in vivo influence their fate. Successful completion of the project will bring new insights to mechanical regulation of NSPCs leading to new insights into brain development and neural stem cell transplant strategies.
