Abstract
Oocyte-to-embryo transition is the process that turns the meiotic arrested oocyte after fertilization into a new developing embryo. The nematode Caenorhabditis elegans is a suitable model organism to study this process, which in this organism is regulated by a protein called MBK-2. In the 1-cell embryo, MBK-2 phosphorylates selected proteins
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that function in meiotic oocyte development, therewith triggering their degradation by proteasomes, thus paving the way to mitotic embryo development. In the meiosis arrested oocyte, MBK-2 is kept quiescent at the cortex by the PTPL protein EGG-3. After fertilization, MBK-2 is released into the cytoplasm, where it is now able to phosphorylate its targets. The work presented here focuses on the mechanisms that drive the dynamic distribution of EGG-3 and MBK-2 in both the oocyte and early embryo, and how this relates to their function. We demonstrate that in diplotene oocytes, MBK-2 is transciently recruited to the nucleus, where it may regulate transcription. In prophase I arrested oocytes MBK-2 is instead recruited to the cortex by its membrane associated anchor EGG-3. EGG-3 is recruited to the plasma membrane along the ER-Golgi secretion pathway in association with the transmembrane protein CHS-1. EGG-3 and CHS-1 are interdependent on each other for their transfer to the plasma membrane. MBK-2 associates with the EGG-3 / CHS-1 complex only after they have been transferred to the oocyte cortex. After fertilization, EGG-3 and MBK-2 are redistributed from the plasma membrane to endosomes in a RAB-5 dependent process. MBK-2 is released from endosome-associated EGG-3 into the cytosol in a RAB-7 dependent process. EGG-3 on the other hand is now sorted to lysosomes by the ESCRT machinery, where it is degraded. Transit of MBK-2 through endosomes is crucial for its release into the cytosol, and interference with this pathway delays the clearance of its target protein OMA-1. Finally, we describe the function of two other PTPL proteins, EGG-4 and EGG-5, in regulating the proper localization, redistribution and functioning of EGG-3, MBK-2 and CHS-1. We propose that MBK-2 functions as a developmental switch at different stages of oocyte development and oocyte-to-embryo transition. Sequential settings of the MBK-2 switch are reflected by its distinct subcellular distributions during oocyte development and egg activation, which are mediated by the EGG-3/4/5 proteins. Although homologues mechanisms have not (yet) been found for other (higher developed) species, we speculate that the regulatory functions of the EGG proteins towards MBK-2 in C. elegans might reflect a common principle, where PTPL proteins mediate the distribution and/or activation of specific kinases during crucial stages of development.
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