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, 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|
|McNally, Francis J (2013) Mechanisms of spindle positioning. J Cell Biol 200:131-40|
|McNally, Karen L P; Fabritius, Amy S; Ellefson, Marina L et al. (2012) Kinesin-1 prevents capture of the oocyte meiotic spindle by the sperm aster. Dev Cell 22:788-98|
|McNally, Karen Perry; McNally, Francis J (2011) The spindle assembly function of Caenorhabditis elegans katanin does not require microtubule-severing activity. Mol Biol Cell 22:1550-60|
|Ellefson, Marina L; McNally, Francis J (2011) CDK-1 inhibits meiotic spindle shortening and dynein-dependent spindle rotation in C. elegans. J Cell Biol 193:1229-44|
|Fabritius, Amy S; Ellefson, Marina L; McNally, Francis J (2011) Nuclear and spindle positioning during oocyte meiosis. Curr Opin Cell Biol 23:78-84|
|Fabritius, Amy S; Flynn, Jonathan R; McNally, Francis J (2011) Initial diameter of the polar body contractile ring is minimized by the centralspindlin complex. Dev Biol 359:137-48|
|McNally, Karen L; Martin, Judy L; Ellefson, Marina et al. (2010) Kinesin-dependent transport results in polarized migration of the nucleus in oocytes and inward movement of yolk granules in meiotic embryos. Dev Biol 339:126-40|
|Roll-Mecak, Antonina; McNally, Francis J (2010) Microtubule-severing enzymes. Curr Opin Cell Biol 22:96-103|
|Johnson, Jacque-Lynne F A; Lu, Chenggang; Raharjo, Eko et al. (2009) Levels of the ubiquitin ligase substrate adaptor MEL-26 are inversely correlated with MEI-1/katanin microtubule-severing activity during both meiosis and mitosis. Dev Biol 330:349-57|
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