Functional genomic studies of Cdk8/CDK19 in development and disease
We are investigating novel roles for Cdk8 family members as well as modeling disease-associated human variants. Our work also shows compelling links between Cdk8 function and familial Parkinsonism. Cdk8 in Drosophila is the orthologue of vertebrate CDK8 and CDK19. These proteins have been shown to modulate transcriptional control by RNA polymerase II. We found that neuronal loss of Cdk8 severely reduces fly lifespan and causes bang sensitivity. Remarkably, these defects can be rescued by expression of human CDK19, found in the cytoplasm of neurons, suggesting a non-nuclear function of CDK19/Cdk8. Here we demonstrate that Cdk8 plays a critical role in the cytoplasm, with its loss causing elongated mitochondria in both muscles and neurons. We show that Cdk8 promotes the phosphorylation of Drp1 at S616, a key component in mitochondrial fission. Intriguingly, Pink1, a mitochondrial kinase implicated in Parkinson's disease, also phosphorylates Drp1 at the same residue. Indeed, overexpression of Cdk8 significantly suppresses the phenotypes observed in flies with loss of Pink1, including elevated levels of ROS, mitochondrial dysmorphology, and behavioral defects. In summary, we propose that Pink1 and Cdk8 perform similar functions to promote Drp1-mediated fission.
See our recent study published in Nature Communications.
This project is a collaboration with the labs of Dr. Hugo Bellen (Baylor College of Medicine) and Dr. Hyunglok Chung (Houston Methodist Research Institute). Funded by the Canadian Institutes of Health Research (CIHR).
See our recent study published in Nature Communications.
This project is a collaboration with the labs of Dr. Hugo Bellen (Baylor College of Medicine) and Dr. Hyunglok Chung (Houston Methodist Research Institute). Funded by the Canadian Institutes of Health Research (CIHR).
Studying cancer in Flies
We have been studying “Hipk” proteins and their regulation of organ growth. Hipk proteins are found in many species including humans. We and others have found that loss of Hipk/Hipk2 in both mice and flies results in reduced proliferation, suggesting that Hipk family members are required for growth. We generated a novel cancer model in flies that is due to having too much Hipk protein. This causes fly organs and limbs to overgrow massively. In addition, cells bud off from these organs and move to new locations within the body, dramatically mimicking what occurs during metastasis of cancers in humans. We are currently trying to understand how Hipk hijacks the normal cellular control mechanisms to cause cells to become rogue and initiate tumors and metastasis. We hope to find ways to reverse the effects of Hipk on cells, leading to the therapies that can be used to treat certain cancers.
See our recent study published in Frontiers in Cell and Developmental Biology.
Funded by the Canadian Institutes of Health Research (CIHR).
See our recent study published in Frontiers in Cell and Developmental Biology.
Funded by the Canadian Institutes of Health Research (CIHR).
Control of organ formation and morphogenesis during development
The long-term goal of my research program is to understand how groups of cells develop into specialized adult organs. Such a process requires regulation of growth, morphogenesis and differentiation. My research group uses the well-characterized, genetically-tractable fruit fly, Drosophila melanogaster, as a model organism. Specifically, we seek to understand how developmental processes are regulated by protein kinases, as precise regulation of signal transduction pathways is often achieved through the reversible phosphorylation of proteins.
Funded by the Natural Sciences and Engineering Research Council of Canada (NSERC)
Modeling Robinow Syndrome in Drosophila and Chick
We are studying autosomal dominant Robinow syndrome (RS), in which genetic changes affecting WNT signaling pathways have been found. Major clinical features include shortening of the limbs and craniofacial abnormalities, suggesting fundamental defects in skeletal tissue organization. In collaboration with Dr. Joy Richman at UBC we are using the chicken embryo and fruit fly to study the links between genotype and phenotype. By expressing human gene variants in animal models, we learn not only about the impact of the mutation on gene function but also about how polarity in vertebrate cells contributes to morphogenesis.
Funded by the Canadian Institutes of Health Research (CIHR).
Funded by the Canadian Institutes of Health Research (CIHR).