| The continual regeneration of many highly differentiated tissues such as blood, skin, and sperm relies on the maintenance of intact stem cell populations throughout adult life. In order to retain regenerative capacity with age, the stem cells must maintain a crucial balance between self-renewal and differentiation. A fundamental characteristic of stem cells that contributes to long-term regenerative potential is their remarkable capacity for asymmetric division, whereby one daughter cell self-renews stem cell identity and the other initiates differentiation. The mechanisms that regulate stem cell asymmetric division are critical to ensure both ongoing renewal of essential tissues and protection from stem cell tumors, yet despite their significance, remain poorly understood. It is hypothesized that both intrinsic and extrinsic mechanisms play important roles in stem cell regulation.; The Drosophila male germ line is an excellent model for genetic analysis of stem cell regulatory mechanisms, as the identity of the stem cells and their physical relationship with surrounding somatic cells are known. I took two approaches to elucidate mechanisms that regulate self-renewing stem cell divisions in the Drosophila male germ line. One approach undertook forward genetic screens to identify in an unbiased fashion genes that control male germ line stem cell divisions. By this approach, I discovered that the essential Drosophila nucleoporin gene nup154 is required for maintenance of male germ line stem cells and other highly proliferative tissues, and described the molecular basis for lethal versus viable but sterile alleles. I also identified from both loss-of-function and gain-of-function screens mutations in genes normally required to either maintain or restrict germ line stem cell self-renewal. In a second approach, I investigated candidate genes encoding molecules in conserved signal transduction pathways for roles in germ line stem cell divisions, possibly acting in the hypothesized stem cell niche. I demonstrated that a Janus kinase (JAK) signaling pathway is required to maintain self-renewal capacity of Drosophila male germ line stem cells upon asymmetric division. Conversely, I showed that Egfr signaling is indirectly required in somatic cells of the niche to ensure differentiation upon asymmetric division, thus restricting self-renewal and controlling germ line stem cell number. |
