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| A major focus of our research is to understand the regulatory mechanisms that govern meiotic progression. A key question of current interest is how the nuclear divisions are coupled with spore wall development. The spindle pole body (SPB) plays a unique role in this process, serving as the initiation site for both spindle assembly and spore wall synthesis. We have previously reported that Spo1, a meiosis-specific phospholipase B (PLB) homolog, is required at several stages of SPB morphogenesis during meiosis and spore formation (Fig. 1-3), and proposed that it may be part of a novel meiosis-specific signaling pathway controlling the dual functions of the SPB during gametogenesis (Tevzadze et al. 1996 Gene 177:253 and 2000 Chromosoma 109:72). PLB enzymes cleave phospholipids generating lysophospholipids and fatty acids, both of which may act as signaling molecules. Several lines of evidence now indicate that phosphatidylinositol (PI) is a likely Spo1 substrate. These include identification of high-copy suppressors of spo1 encoding glycosylphosphatidylinositol(GPI) lipid-anchored proteins (e.g., Cwp1 and Spo19, Fig.4-5), partial suppression by PLB3 (a recently identified PI-specific PLB, Fig. 6) when expressed from the SPO1 promoter, and genome-wide analysis showing that Spo1 is one of 30 strong PI-binding proteins in budding yeast (Zhu et al.; 2001 Science 293: 2101). Mutant suppressors that allow sporulation of spo1 (Fig. 7) have further led to detection of two putative downstream targets (sms-mutants, Fig. 8). One, identified as SPO73, has an unexpected phenotype. It is essential for sporulation in the presence of Spo1 and inhibits spore formation in its absence . Spo73 contains a high-potential iron-sulfur protein (HPIP) domain required for both its positive and negative activities. This type of HPIP domain is found in only two other yeast proteins, Tor1 and Tor2 (PI3 kinase homologs) which are protein kinases regulating growth in response to lipid signals. The similar HPIP domains in the Tor-kinases and Spo73 (which is not a kinase), suggest these proteins act via a common mechanism to sense and transmit PI-derived signals. In the presence of Spo1, Spo73 allows for the progression of meiosis in wild-type cells. When the Spo1-dependent pathway controlling SPB morphogenesis is defective (i.e. in a spo1 mutant), Spo73 acts negatively, as part of a novel checkpoint-like control to inhibit spore formation (Fig. 9). Current studies are aimed at testing this model and at isolating additional putative targets of the Spo1 signal that may affect other aspects of SPB development during sporulation. This work has implications for how cell cycle and differentiation programs interact and how cellularization is regulated. |
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