Research Area

Identification of Interwined functions of separase and caspase in chromosome separation and programmed cell death

Timely sister chromatid separation, promoted by separase, is essential for faithful chromosome transmission during mitosis and meiosis. We report that the C. elegans pro-apoptotic caspase CED-3, which was previously known exclusively for its role in regulating apoptosis, cleaves cohesin SCC-1 specifically and functions with separase SEP-1 to allow mitotic and meiotic chromosome separation. CED-3 function alone is necessary for the normal rate of embryonic development and germline meiotic chromosome disjunction independent of its role in apoptosis. Loss of the endogenous soma-specific (CSP-3) and germline-specific (CSP-2) caspase inhibitors results in CED-3-dependent suppression of embryonic lethality and meiotic chromosome non-disjunction, respectively, in animals compromised for separase function. Further, removal of SEP-1 blocks developmental apoptosis and suppresses a mutant defective for the apoptotic suppressor ced-9/Bcl-2. Thus, caspases and separases orchestrate both apoptosis and chromosome segregation, supporting the view that co-option of components in chromosome segregation may have led to the innovation of programmed cell suicide early in metazoan evolution.

2, Identification of transdifferentiation regulatory genes by AID (Auxin-Inducible Degradation) system. 

The major objectives of the research are to illuminate the cellular and molecular mechanisms that control plasticity of developing and differentiated cells in vivo and to investigate how post-mitotic differentiated cells can be transdifferentiated and remodeled into new cell types. The well-elucidated pathway for endoderm development in C. elegans will be applied to the molecular dissection of transdifferentiation (conversion of one organ into another). One component in this pathway, the ELT-7 GATA-type transcription factor, is capable of overriding the embryonic multipotency commitment transition (“MCT”), which normally locks cells into their differentiated states and prevents them from being reprogrammed. ELT-7 can cause differentiated pharynx cells in adults to be remodeled into cells with ultrastructural characteristics, and gene expression patterns, of intestinal cells, without intercession of a dedifferentiated intermediate or cell division. I have adapted the auxin-inducible degradation (AID) system for investigation of transdifferentiation regulatory mechanisms.