My genuine interest in biology is to understand how the activity of an entire genome is regulated. It is amazing that this regulatory mechanism autonomously works mostly without any mistakes.
|This slide show gives you an overview of early Drosophila development from fertilization to establishment of segmentation. It takes about 3 hours. The entire embryogenesis takes about one day. The embryos were stained with antibodies that recognize the Engrailed protein. Engrailed proteins are expressed in each segment so that we can see how segmentation proceeds in the embryo. Notice the dynamic movement of cells. Anterior is to the left, and dorsal is to the top.|
In my laboratory, I pursue this goal using the fruit fly Drosophila melanogaster. This tiny fly, often found in my kitchen and yours, has enormous potential in biomedical science. After our fly community (Drosophila researchers) sequenced and polished the entire Drosophila genome (Adams, et al. 2000), we found that about 61% of human disease genes exist in Drosophila (Rubin, et al. 2000). This means that this small creature can be used for finding cures for human diseases. Moreover, the use of Drosophila allows us to take research strategies that cannot be applied to humans or other mammalian models. In particular, genetics is the one that stands out from the others.
Gene activities are influenced by different factors in the cell. A gene must be transcribed in the nucleus. There are many steps to go through before an active protein is made. Each step may have an important biological meaning. I pursue the following three questions:
is the hedgehog signal pathway regulated?
How are the blood cells produced in Drosophila?
How does evolution act on pre-mRNA processing?
Briefly (click on each question if you want to know more about it)....
I aim to understand how an extracellular signaling molecule turns on (or off) gene transcription in the nucleus in the first project. My model system is the hedgehog signal transduction pathway. Note that hedgehog means here the name of an important gene in Drosophila as well as in humans, not of a small mammal. Malfunction of human hedgehog genes (three of them in total) cause many serious inheritable diseases. I want to know how many different proteins are involved in this pathway and to understand how they function together in a coordinated manner. In my laboratory, I am working on two genes (found by myself) called oroshigane and shanti, which are likely to work in the hedgehog pathway.
For the second question, I am working on the gene called semushi. This gene again has homologues in many organisms including humans. This gene encodes a protein that modifies other proteins with a single molecule called SUMO. This modification controls a variety of cellular functions such as nuclear transport. I am particularly interested in its involvement in hematopoiesis, blood cell development, because Cactus protein, a homologue of human IkB, is a target in this modification system. The system involving IkB is known to be important for immune and inflammatory responses as well as hematopoiesis. Taking advantage of the Drosophila system, I want to identify genes that work in hematopoiesis, so that I will gain insight into molecular mechanisms of development of human blood cell diseases such as leukemia.
Lastly, I want to establish a link between conserved DNA sequences during evolution and their biological functions. Conservation in evolution means that similar DNA sequences are found in related, sometimes distant, species. What this suggests to scientists is that there are some hidden biological roles for such conserved segment of DNA. Using the Drosophila Alcohol dehydrogenase (Adh) as a model, I hope to find such relationship between the level of Adh activity and conserved segments in introns (segments to be removed by splicing). The idea here is whether these segments play a role during splicing. I make mutations in vitro (in a test tube) to disrupt the conservation and test if they have any effect for (or against) splicing. It should be pointed out that many human diseases are due to splicing defects. Tests are done in Drosophila tissue culture cells and in flies by creating transgenic Drosophila.