STEM CELLS AND DIFFERENTIATION. Stem cells produce the cells that will eventually form the tissues and organs of multicellular organisms. The property that distinguishes stem cells from other cell types is that they can self-renew at each mitotic division while also producing daughter cells that differentiate into specialized cells. Stem cells by their nature are difficult to study; their numbers are small and they are often in inaccessible locations. We study one group of stem cells, the germline stem cells in Drosophila, in order to understand how they maintain identity and how daughter cells undergo differentiation during oogenesis. In Drosophila, these cells occupy a specific position in the ovary and can be studied by genetics, molecular and cell biology. Oogenesis initiates when a stem cell daughter (cystoblast) divides precisely 4 times with incomplete cytokinesis to produce a "cyst" of 16 interconnected cells. By studying mutations that disrupt stem cells and cysts and cloning the affected genes, we have begun to understand the pathways that regulate stem cells and cyst formation (McKearin, BioEssays, 1997).
Increasingly, the work in my lab has focused on the earliest-acting gene in the cyst formation pathway, the bag-of-marbles gene. In bam mutants, the germline becomes hyperplastic because all germ cells continue to behave like stem cells. The highly restricted expression of bam mRNA and protein indicate that Bam is required in the specialized stem cell daughter, the cystoblast. In fact, a combination of bam misexpression and loss-of-function experiments showed that Bam is both necessary and sufficient for cystoblast development. Recent data shows that a transcriptional silencer keeps bam ?off? specifically in the stem cell (Chen & McKearin, 2002). Our current efforts have focused on identifying the proteins that bind to the bam silencer element as these represent "stem cell" factors.
We have learned that Bam is an essential component of a germ cell specific organelle, termed the fusome, which regulates critical aspects of germ cell development. One of its roles appears to be that of a specialized endoplasmic reticulum that requires Bam for proper function. One set of projects focuses on how differentiation depends on fusome function which in turn depends on Bam. In addition, we have identified new genes and proteins that work with Bam to regulate blast cell differentiation. We have cloned one of these, the bgcn gene, and learned that it is required specifically for Bam protein localization and function. Furthermore, Bam and Bgcn proteins interact biochemically and thus work together in complex to promote cystoblast differentiation. By understanding the Bam/Bgcn pathway of cystoblast activation, we expect to reveal the factor(s) that make stem cells different from their specialized derivatives.
RESEARCH INTERESTS
development of germ cells
stem cell biology
signaling controlling cell fate
RECENT PUBLICATIONS
Chen, D. and McKearin, D.M., "Dpp signaling silences bam transcription directly to establish asymmetric divisions of germline stem cells" Current Biology, 13:1786-1791, 2003
Chen, D. and McKearin, D. M., "Gene circuitry of a stem cell niche" submitted, 2004
Jiang F, Ye X, Liu X, Fincher L, McKearin D, Liu Q, "Dicer-1 and R3D1-L catalyze microRNA maturation in Drosophila" Genes and Development, 19:1674-1679, 2005
Maines, J. Z., Park, J. K., Wiliams, M., McKearin, D. M., "Stonewalling Drosophila Stem Cell Differentiation by Epigenetic Controls" Development, 134:1471-1479, 2006
Park, J., Liu, X., Strauss, T., Jiang, F., Liu, Y., McKearin, D.M. and Liu, Q., "Loquacious-dependent microRNAs control Drosophila germline stem cell maintenance." Current Biology, 17:1-6, 2006
SIGNIFICANT PUBLICATIONS
Lavoie, C., Ohlstein, B. and McKearin, D.M., "Localization and function of Bam protein requires the activity of the benign gonial cell neoplasm gene." Devel. Biology, 212:405 - 413, 1999
Ohlstein, B., Lavoie, C., *Vef, O., *Gateff, E. and McKearin, D.M., "The Drosophila cystoblast differentiation factor, benign gonial cell neoplasm, is related to DExH-box proteins and interacts genetically with bag-of?marbles." Genetics, 155:1809 - 1819, 2000
Clark, K.A. and McKearin, D.M., "The Drosophila stonewall gene encodes a putative transcription factor essential for germ cell development" Development, 122:937 - 949, 1996
Ohlstein, B. and McKearin, D.M, "Ectopic expression of the Drosophila Bam protein eliminates germline stem cells" Development, 124:3651 - 3662, 1997
Chen, D. and McKearin, D.M, "A Discrete Transcriptional Silencer in the bam Gene Determines Asymmetric Division of the Drosophila Germline Stem Cell" Development, 130:1159-1170, 2003
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