Stem cells are characterized by their abilities to self-renew and to produce numerous differentiated daughter cells. These two special properties enable stem cells to play a central role in generating and maintaining most tissues in higher organisms. Over-proliferation of stem cells is the leading cause of cancer while under-proliferation of stem cells leads to tissue dystrophy, anemia, immuno-deficiency, or infertility. Drosophila and the mouse represent two powerful systems for studying stem cells since they allow easy access to combined genetic, cell biological, and molecular analyses.

We use Drosophila as a pilot model to explore molecular mechanisms underlying stem cell division, and the mouse as a comparative model to expand what we learn from Drosophila to mammalian systems. Our research begun with the identification of germline stem cells in the Drosophila ovary and demonstration of their self-renewing asymmetric division. We showed that the asymmetry of the stem cell division is marked by the spectrosome – a novel membrane skeleton-rich organelle that segregates predominantly to the daughter stem cell during the division. The asymmetric division of germline stem cells in Drosophila requires intracellular mechanisms involving the spectrosome as well as genes such as pumilio, bag-of-marbles (bam), nanos, and arrest/Bruno. Moreover, germline stem cell division is controlled by signals emanating from an apical somatic signaling center. The somatic signaling is mediated by the fs(1)Yb,   piwi, and hedgehog genes that are expressed in the signaling cells. Among them, piwi defines the first family of evolutionarily conserved genes (the piwi, a.k.a., argonuate gene family) that are essential for stem cell division in both animal and plant kingdoms. Interestingly, the same signaling center also regulates the division of somatic stem cells in the ovary through the action of a Yb-mediated hedgehog signaling pathway. Thus, the fly ovary is also an excellent model for studying how the divisions of two distinct types of stem cells within an organ is controlled – a question central to the understanding of organogenesis and homeostasis.

Currently, we are conducting molecular analysis in Drosophila to probe how the intra- and intercellular mechanisms regulate the asymmetric division of the germline and somatic stem cells. Meanwhile, we are systematically investigating how the findings from the Drosophila research are relevant to mammalian systems. Particularly, we focus on the function of mammalian members of the piwi family genes in germline stem cell divisions in mice and humans. These studies begin to reveal evolutionarily conserved mechanisms that regulate stem cell division.

In addition to the stem cell projects, we are working the function of stem cell genes in other events during germline development. For example, piwi also plays an important role in the determination of the germline lineage during Drosophila embryogenesis. A murine homolog of piwi, called miwi, is a master regulator of spermiogenesis. Overexpression of hiwi is highly correlated to seminomas, a testicular cancer of high fatality. These projects provide additional opportunities for us to understand molecular mechanisms shared by stem cells and other developmental processes.

E-mail
h.lin@cellbio.duke.edu

412 Nanaline Duke Bldg., Box 3709
Duke University Medical Center
Durham, NC 27710

Telephone
919-684-3169
Fax
919-684-5481

Selected Publications
Wang, Z and Lin, H. (2005) The division of Drosophila germline stem cells and their precursors requires a specific cyclin. Current Biology (in press)

Szakmary, A., Cox, D. N., Wang, Z. and Lin, H. (2005) Regulatory relationship between piwi, pumilio and bag-of-marbles in Drosophila germline stem cell self-Renewal and differentiation. Current Biology (in press)

Asaoka, M. and Lin, H. (2004) Germline stem cells in the Drosophila ovary descend from pole cells in the anterior region of the embryonic gonad. Development 131, 5079-5089.

Wang, Z and Lin, H. (2004) nanos maintains germline stem cell self-renewal by preventing differentiation. Science 303, 2016-2019. [Highlighted by Nature Reviews Mol. Cell Biol. (2004) 5, 253   & Nature Reviews Genetics (2004) 5, 244-245]

Kuramochi-Miyagawa, S., Kimura, T., Ijiri, T., Asada, N., Fujita, Y., Ikawa, M., Isobe, T., Iwai, N., Okabe, M., Deng, W., Lin, H., Matsuda, Y. and Nakano, T. (2004). Mili, a mammalian member of piwi family gene, is essential for spermatogenesis. Development 131, 839-849.

Lin, H. (2004) Female germline stem cells in Drosophila. In "Handbook of Embryonic Stem Cells". (Gearhart, J.D. et al. Eds.). Academic Press, pp 157-170.

Lin, H. (2004) Stem cells in the germline. In "Stem cell Handbook" (S. Sell ed.). Humana Press, Inc. pp 57-74.

Smulders-Srinivasan, T. and Lin, H. (2003) Screens for piwi suppressors in Drosophila identify dosage-dependent regulators of germline stem cell division. Genetics 165, 1971-1991.

Lin, H. (2003). To be and not to be. Nature 425, 353-355.

Deng, W. and Lin, H. (2002) miwi, a murine homolog of piwi, encodes a cytoplasmic protein essential for spermatogenesis. Developmental Cell 2, 819-830.

Qiao,D., Zeeman, A.-M., Deng, W., Looijenga,L.H.J. and Lin, H. (2002) Molecular characterization of hiwi, a human member of the piwi stem cell gene family whose overexpression is correlated to seminomas. Oncogene 21, 3988-3999. [Highlighted by major news media sources such as Reuters, NBC, CNN, BBC, etc.]

Lin, H. (2002). The stem cell niche theory: lessons from from flies. Nature Review Genetics 3, 931-940.

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Undergraduate Students:

Kevin Ma, Computer support.