"You have made your way from worm to man, and much within you is still a worm" (Nieztsche)
Research
Introduction
My lab uses C. elegans genetic approaches to better understand genetic pathways relating to C. elegans germ cell development and integrity as well as on DNA damage response pathways needed for maintaining the genome integrity of germ cells. Furthermore, we developed a focus on C. elegans models for dopaminergic neurodegeneration which is the key pathology of Parkinson's disease. In addition, we established collaborations within the Dundee College of Life Sciences (CLS) and the Dundee Medical School to complement our genetic studies and to aid other labs in efficiently using the C. elegans model. We use a "whole organism" based approach to study cellular phenotypes in their natural context. C. elegans is the simple most animal system allowing for forward genetic screening, and is unique in allowing for genome wide RNAi screening where RNAi is applied at the organismal level.
Apoptosis is particularly important during germ cell development. In mammals, programmed cell death leads to the elimination of more than 99.9% of oocytes. Germ cell apoptosis is thought to contribute to the integrity of future generations by eliminating unwanted or damaged germ cells. Failure to induce germ cell apoptosis leads to increased levels of congenital diseases while excessive germ cell apoptosis contributes to infertility. Despite the importance of germ cell apoptosis we know relatively little of how it is controlled. In mammals, analysis of germ cell apoptosis in the context of an entire organism is largely limited to reverse genetic approaches, and cell culture models often fail to recapitulate cellular behaviour in intact tissues. Apoptosis is also a common feature of the DNA damage response to eliminate unwanted or genetically compromised cells whose persistence might compromise the survival of the entire organism. Hence the ability to induce apoptosis and other DNA damage responses is often lost in cancer cells. Excessive apoptosis or other forms of cell death contribute to neurodegeneration and are evident in condition like Parkinson's disease.
I started working on C. elegans in the laboratory of Michal Hengartner in Cold Spring Harbor. Our work was based on the seminal work of the Horvitz lab that established a genetic pathway that affects the vast majority of the 131 programmed cell deaths that occur during the somatic development of the worm. We focused our attention on the C. elegans germ line, which is the only proliferative tissue in adult worms and started looking at germ cell apoptosis. We were the first to discover that germ cell apoptosis in C. elegans occurs in response to genotoxic insults and requires the same core apoptosis machinery as used for developmental apoptosis. In addition, we defined several mutants specifically defective in DNA damage induced apoptosis and cell cycle arrest (link to paper).
In my first independent lab, in Munich, with the help of my PhD students Björn and Arno, who now have accepted PI positions in their own right, we cloned and genetically characterized the C. elegans clk-2 checkpoint gene (link to paper). As part of a collaborative effort, initiated by Simon Boulton at the time in Marc Vidal's lab using functional-genomics and RNAi-based approaches, we showed that conserved genes, previously implicated in yeast checkpoint signalling, also function in C. elegans DNA damage response pathways (link to paper). Furthermore, we cloned and characterized the worm homolog of the mammalian p53 oncogene termed cep-1 (link to paper), and we defined two transcriptional targets of cep-1/p53, namely egl-1 and ced-13, both of which contribute to irradiation induced germ apoptosis by antagonizing ced-9/bcl-2 (link to paper). We recently wrote a comprehensive review on C. elegans germ cell apoptosis (link to paper). In addition, we engaged in several collaborative projects relating to using the C. elegans germ line to study meiotic recombination and chromosome pairing (links to paper) and performed the initial genetic screen that recently allowed implicating prom-1 as a new meiosis regulator (link to paper).
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