The process of sexual reproduction involves a host of requirements that must be met before an oocyte and sperm can fuse together to form a zygote capable of further functional development.  One such requirement that remains incompletely understood, despite years of study in multiple model organisms, is the complex cellular program of meiosis.  Meiosis is the specialized cell cycle by which the haploid gametes (oocytes and sperm) are produced.  It is not only of crucial importance to successful sexual reproduction or propagation of a species, but also to human health.  Defects during the meiotic divisions have serious deleterious outcomes such as infertility, spontaneous miscarriages, birth defects (such as Down Syndrome), and even tumorigenesis.  In addition, many of the mechanisms that regulate meiosis are reutilized in the mitotic cell cycle, and improper regulation of mitosis is a critical factor in many diseases, such as cancer.  Furthermore, comparisons of the general strategy and currently known factors involved in meiosis shows a high degree of evolutionary conservation between mammals and more amenable model organisms such as Drosophila and Caenorhabditis elegans.

We utilize the nematode C. elegans and are taking an interdisciplinary approach involving genetics, molecular biology, cytological, and biochemical techniques to study two specific aspects of meiosis, oocyte meiotic arrest and oocyte maturation.  In a majority of sexual reproducing animals, the female meiotic cycle involves a characteristic arrest that is alleviated at a later time point to ensure the proper coordination of oocyte maturation and fertilization such that no precious oocyte is wasted.  Cyclin-dependent kinases (Cdks) are universal regulators of both mitotic and meiotic cell cycle progression in eukaryotes.  It is a complex of Cdk1 and cyclin B, termed maturation promoting factor (MPF), that acts to drive the meiotic cell cycle forward.  It is essential that the MPF complex be kept in an inactive state until maturation is required, which is accomplished via inhibitory phosphorylations of Cdk1 by the Wee1/Myt1 family of kinases.  In C. elegans, when oocytes are depleted of the Myt1 ortholog, WEE-1.3, the animals exhibit precocious oocyte maturation, consisting of premature nuclear envelope breakdown and chromosome over-congression where the chromosomes have coalesced into a single mass of chromatin, and are fertilization incompetent and thus, infertile.

Currently there are many questions regarding WEE-1.3 function, including:

– why precocious oocyte maturation results in fertilization incompetent oocytes

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– what additional regulators or interactors of WEE-1.3 and CDK-1 exist in the oocyte maturation pathway.  

 C. elegans is an ideal system to study oocyte maturation as many aspects of gametogenesis and embryogenesis can be observed directly in a living animal.  As function is conserved in the currently identified meiotic pathways across the animal kingdom, C. elegans is ideal for identifying novel components of oocyte meiotic maturation and cell cycle regulation.  The information gained from these studies will not only contribute to our understanding of the events of meiosis and fertilization, but will strongly benefit multiple fields- the reproductive medicine, the cell cycle, and the cancer fields.

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