The primary focus of our research is to understand the mechanisms controlling stem cell behavior. Stem cells are the building blocks of development and provide for the maintenance and regeneration of tissues, such as blood, skin, and sperm, throughout the lifetime of an individual. The ability of stem cells to contribute to these processes depends on their ability to divide and generate both new stem cells (self-renewal) as well as specialized cell types (differentiation). The decision between self-renewal (proliferation) and differentiation must be tightly controlled. If too many cells differentiate, the stem cell population may become depleted and tissues cannot be maintained. Alternatively, unchecked self-renewal could expand the number of proliferating, partially differentiated cells in which secondary mutations may arise, leading to tumorigenesis. We are using the process of spermatogenesis in Drosophila melanogaster as a model system to establish paradigms for how stem cell behavior is controlled. The adult testis is a long coiled tube filled with all of the stages of spermatogenesis, with the stem cells and cells going through mitotic amplification divisions at the apical tip, followed by differentiating spermatocytes and spermatids (Figure 1A). In the adult, 6-9 germ line stem cells (GSCs) lie at the tip of the testis in a ring closely surrounding a cluster of post-mitotic somatic cells called the apical hub (Figure 2). When a male GSC divides, it normally gives rise to one cell that will retain stem cell identity (self-renewal) and one cell, called a gonialblast, which is displaced away from the hub and will initiate differentiation. Because the stem cells can be easily located at the tip of the Drosophila testis, it is possible to study these cells in the context of their normal environment, also known as the stem cell niche.
Drosophila provides
a powerful genetic system for the identification of genes required for normal
male GSC behavior. Using an unbiased genetic approach,
a biased candidate approach and now genomics, we have begun to
identify intrinsic and extrinsic factors that influence this critical cell
fate choice
between renewal of stem cell identity and initiation of differentiation.
We have previously demonstrated that the Janus kinase (JAK)-Signal
transducer and activator of transcription (STAT) signal transduction pathway
is required
for stem cell self-renewal in the Drosophila testis. In addition
we have shown that the somatic hub cells at the apical tip of the
testis are a primary
component of the stem cell niche that supports self-renewal of
the GSCs. The hub cells express the ligand Unpaired (Upd), which
activates the JAK-STAT
pathway Figure 2: Immunofluorescence image of the tip of a Drosophila testis. Eight germline stem cells (arrowhead shows one) can be seen surrounding a group of specialized somatic cells called the apical hub (red). The hub cells are a critical component of the stem cell niche, as they secrete growth factors that direct stem cell self-renewal.
Being able to study the behavior of stem cells in vivo allows us to begin to ask questions about how the environment can control stem cell self-renewal and survival. The long term goals of this basic research include understanding the mechanisms that are required for maintaining stem cell identity in an effort to develop protocols for long term maintenance of stem cells in culture. Also, a better understanding of how proteins act to direct differentiation, and the order in which they are needed, will help develop methods for leading stem cells down specific differentiation pathways in vitro. Tissue replacement therapy, also known as stem cell therapy or regenerative medicine, can be defined as a part of a group of new techniques or technologies that rely on replacing diseased or dysfunctional cells with healthy ones. In the future, these new techniques may be applied to a wide range of human disorders, including many types of cancer, spinal cord injuries, diabetes, and neurological diseases such as Parkinson's Disease. However, there are many fundamental questions that remain to be answered before the powerful potential of stem cells can be utilized in medical therapies. D.
L. Jones. Stem Cells: So what's in a niche? (2001). Curr. Biol.
11: A.
A. Kiger*, D. L. Jones*, C. Schulz, M. B. Rogers, M.T. Fuller (2001). Y.M.
Yamashita, D.L.Jones, and M.T. Fuller (2003). Spindle orientation by Y.Yamashita,
M.T.Fuller, and D.L.Jones (2005). Signaling in stem cell D.L. Jones, G. Hime, A.P. Mahowald,B. B. Gore, Y. Yamashita, and M.T. Dr. Jones received her PhD in Microbiology and Molecular Genetics from Harvard University. She then carried out her postdoctoral work at the Centre for Developmental Genetics at the University of Sheffield and then in the Department of Developmental Biology at Stanford University as a Lilly Fellow of the Life Science Research Foundation. |
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in the adjacent GSCs to specify stem cell self-renewal.
Ectopic expression of Upd in early germ cells results in testes
filled with thousands
of small cells resembling germ line stem cells and gonialblasts
(Figure 1B).
