Our goal is to understand the mechanisms that position female meiotic spindles at the egg cortex and that mediate polar body formation. In the long term, we hope to elucidate the reasons why asymmetric meiotic spindle positioning is so conserved across animal phyla. The specific goals of this proposal are to elucidate the detailed mechanisms of three distinct pathways that mediate meiotic spindle positioning and polar body formation in Caenorhabitis elegans. 1) Kinesin-1 heavy chain, kinesin light chains and a novel protein called KCA-1 are each required to move the meiotic spindle to the egg cortex before the metaphase-anaphase transition. In contrast, movement of the meiotic spindle to the egg cortex after the metaphase-anaphase transition is kinesin-independent. We will use fluorescence microscopy and in vitro biochemistry to test the hypothesis that a kinesin/KCA-1 complex directly transports the spindle along cytoplasmic microtubules and that a distinct mechanism is responsible for both spindle translocation in the absence of kinesin and spindle rotation during wild-type meiosis. 2) Complete loss of the microtubule-severing protein, katanin, results in failure to assemble a meiotic spindle whereas partial loss of katanin function results in abnormally long meiotic spindles and abnormally large polar bodies. We will use fluorescence microscopy and genetics to test the hypothesis that microtubule-severing activity restricts meiotic spindle length and thereby polar body size. 3) SPE-11 is a sperm protein introduced into the egg at fertilization and which is required for polar body formation. We will use a combination of fluorescence microscopy and genetics to test the hypothesis that SPE-11 mediates polar body formation by interacting with conserved cytokinesis regulators in the egg. Meiotic spindles are relevant to public health for two major reasons. First, abnormal meiotic spindle function leads to aneuploidy that causes Down syndrome and miscarriage. Second, the potential for treating numerous human diseases with patient-matched stem cells is currently limited by abnormal meiotic spindle assembly during animal cloning. A detailed molecular understanding of meiotic spindle function could thus lead to treatments that prevent birth defects and that allow stem cell therapy of human diseases. ? ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Nuclear Dynamics and Transport (NDT)
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Rodewald, Richard D
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University of California Davis
Anatomy/Cell Biology
Schools of Arts and Sciences
United States
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McNally, Francis J; Roll-Mecak, Antonina (2018) Microtubule-severing enzymes: From cellular functions to molecular mechanism. J Cell Biol 217:4057-4069
Nithianantham, Stanley; McNally, Francis J; Al-Bassam, Jawdat (2018) Structural basis for disassembly of katanin heterododecamers. J Biol Chem 293:10590-10605
Vargas, Elizabeth; McNally, Karen; Friedman, Jacob A et al. (2017) Autosomal Trisomy and Triploidy Are Corrected During Female Meiosis in Caenorhabditis elegans. Genetics 207:911-922
McNally, Francis J (2017) Competing chromosomes explain junk DNA. Science 358:594-595
Panzica, Michelle T; Marin, Harold C; Reymann, Anne-Cecile et al. (2017) F-actin prevents interaction between sperm DNA and the oocyte meiotic spindle in C. elegans. J Cell Biol 216:2273-2282
Flynn, Jonathan R; McNally, Francis J (2017) A casein kinase 1 prevents expulsion of the oocyte meiotic spindle into a polar body by regulating cortical contractility. Mol Biol Cell 28:2410-2419
McNally, Karen Perry; Panzica, Michelle T; Kim, Taekyung et al. (2016) A novel chromosome segregation mechanism during female meiosis. Mol Biol Cell 27:2576-89
Cortes, Daniel B; McNally, Karen L; Mains, Paul E et al. (2015) The asymmetry of female meiosis reduces the frequency of inheritance of unpaired chromosomes. Elife 4:e06056
Crowder, Marina E; Flynn, Jonathan R; McNally, Karen P et al. (2015) Dynactin-dependent cortical dynein and spherical spindle shape correlate temporally with meiotic spindle rotation in Caenorhabditis elegans. Mol Biol Cell 26:3030-46
McNally, Karen; Berg, Evan; Cortes, Daniel B et al. (2014) Katanin maintains meiotic metaphase chromosome alignment and spindle structure in vivo and has multiple effects on microtubules in vitro. Mol Biol Cell 25:1037-49

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