During female meiosis, 3/4 of the chromosomes are eliminated and only 1/4 of the chromosomes are inherited by a single egg. In contrast, all chromosomes are distributed among 4 sperm during male meiosis. The elimination of 3/4 of the genome to allow inheritance of only 1/4 of the chromosomes is conserved in all animal phyla, suggesting some fundamental selective advantage. The long-term goals of this project are to elucidate the molecular mechanisms of chromosome elimination and elucidate the selective advantages of asymmetric meiotic division. Errors in meiosis lead to the absence of one chromosome (monosomy) or the presence of an extra chromosome (trisomy) in 10-30% of human conceptions with the majority of these aneuploidies leading to embryonic death. By elucidating the mechanisms of meiotic chromosome elimination in C. elegans, we will identify mechanisms likely to be defective during human meiosis. In this project we will pursue 4 specific aims: 1. Elucidate mechanisms that prevent the sperm aster from capturing the oocyte meiotic spindle. 2. Determine how cytoplasmic dynein orients one spindle pole at the cortex. 3. Determine how katanin mediates acentriolar spindle pole assembly. 4. Test whether unpaired chromosomes are selectively extruded into polar bodies to prevent trisomy.
These aims will be addressed by time-lapse imaging of fluorescent protein fusions within meiotic embryos that have been depleted of key cytoskeletal regulators and cell-cycle regulators by RNA interference and by protein biochemistry.
The proposed research is relevant to public health because chromosomes are missing or an extra chromosome is present in 10-30% of human conceptions. The majority of these chromosomal abnormalities are caused by defects during female meiosis and these chromosomal abnormalities lead to embryonic death or mental retardation. The proposed research will reveal mechanisms that may cause these abnormalities in humans and will suggest ways to prevent them.
|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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