Centriole, centrosome and cilium are interconnected subcellular organelles with shared developmental programs, physiological roles and evolutionary fate. Their malformation leads to infertility and multiple developmental disorders and associates with cancer. How these organelles form in the cell and inherited during fertilization are poorly understood. We are interested in exploiting the many unique aspects of these organelles in Drosophila, to interrogate poorly understood aspects of their biogenesis in general.
Centriole number is usually precisely regulated and a normal cell has exactly two centrioles. In most animals, including humans and flies, a single functional centriole is inherited only from the male sperm. But to date, the origin of the second cellular centriole remains a mystery. We have recently demonstrated the presence of a centriole precursor, named the Proximal Centriole-Like structure (or PCL), during sperm formation in Drosophila melanogaster (fruit flies). Now, the hypothesis that this new structure is inherited during fertilization and is the precursor of the second cellular centriole will be tested.
Another unknown aspect of centriole formation is how they duplicate. In preparation for cell division, each centriole pair duplicates precisely once. Centrioles duplicate in a unique way by forming a single daughter centriole, which develops perpendicularly to the mother centriole. The mechanism underlying this process is not known. Our laboratory has also recently shown that the PCL is a useful model for studying centriole duplication. Because the PCL resembles an early centriole precursor, it provides a unique window into the transient and rarely observed event of centriole formation.
We have recently described the isolation of a new mutation of the centrosomal protein, Asterless. By analyzing this new mutation and re-investigating previously identified asterless mutations, we determined that asterless is necessary for centriole duplication. Furthermore, by exploiting the unique biology of centrioles contained within sperm stem cells, we developed a new method that demonstrated asterless as a key player in early centriole formation.
An additional project in our laboratory that is currently underway uses Drosophila genetics to address the question of how centrioles elongate from a short procentriole to a long mature centriole. During spermatogenesis, Drosophila centrioles elongate dramatically to form giant centrioles. Since these centrioles grow to a size that can be easily and robustly observed under simple light microscopy, we have been able to identify mutants that interfere with centriole elongation.
We are also interested in developing a method to reconstitute centriole formation in vitro. Drosophila embryo centrioles are unique because they contain a stable cartwheel structure that lends itself well to biochemical analysis. By exploring this structure, we showed that Sas-6, a known component of the cartwheel, forms a tetrameric structure and is likely to be a component of the cartwheel central tubule. We proposed, based on this and other findings, that the central tubule of the cartwheel is a helical structure.
|
Harvard University Home / GSAS Home / HMS Home 
