Grant: Project Grant

Cell division is essential for development, allowing one cell, the fertilized egg, to give rise to the roughly 37 trillion cells that make up the adult human body. In adults, cell division sustains organ function, particularly in tissues like the gut, where new cells are needed to replace the lining of the intestine every few weeks, or the liver, where damaged cells are replaced continuously. Proper chromosome segregation during cell division ensures that each daughter cell gets exactly one copy of the replicated genome. Errors in chromosome segregation can compromise the ability of cells to perform their normal functions and, in some cases, can lead to diseases such as cancer. This proposal focuses on the spindle assembly checkpoint, a key regulator of cell division that helps cells prevent chromosome segregation errors. In particular, we want to know how the strength of the spindle assembly checkpoint is regulated, since this attribute is critical to its ability to safeguard chromosome segregation, yet what determines checkpoint strength is poorly understood. We use the small nematode worm, C. elegans, as a model system, because it allows experimental approaches that are challenging in mammalian models and not possible in human subjects. We use microscopy, in combination with genetic tools, to dissect the determinants of checkpoint strength in different cell types and at different stages of development in the context of a living, intact animal. As many C. elegans genes perform conserved functions in humans, and key regulators of cell division have been discovered in C. elegans, it is highly likely that the mechanisms uncovered here will be important for understanding how checkpoint strength is regulated in human cells. In the long-term, this knowledge may lead to therapies to modulate checkpoint activity, which could be used to improve cell division in stem cells or to disrupt it in cancer cells.