Wellcome Investigator in Science and Professor of Cell Biology
Hiro Ohkura is a Wellcome Investigator in Science and Professor of Cell Biology at the University of Edinburgh. His group is studying the molecular regulation of meiotic chromosomes and spindle in oocytes using Drosophila as a model system. Hiro did his PhD study on fission yeast mitosis in Prof Yanagida's lab in Kyoto University, Japan. He then worked as a postdoc in Prof Glover's lab in Dundee University, UK, studying Drosophila mitosis as well as fission yeast mitosis. He was awarded a Wellcome Senior Fellowship in 1997 and has established his lab in the University of Edinburgh, UK. He held a Wellcome Senior Research Fellowship for 20 years before becoming a Wellcome Investigator in 2018.
The meiotic spindle and chromosomes in oocytes
Accurate segregation of chromosomal DNA is essential for life. An error in this process could result in cell death or aneuploidy. Furthermore, chromosome segregation in oocytes is error-prone in humans, and mis-segregation is a major cause of infertility, miscarriages and birth defects. Chromosome segregation in oocytes shares many similarities with those in somatic divisions, but also has notable differences. Distinct features of oocytes potentially hinder accurate chromosome segregation. They include (1) lack of centrosomes, the major microtubule nucleation centres in mitosis, (2) exceptionally large cell volume, and (3) cell cycle arrests at two stages. Oocytes are likely to have specific molecular mechanisms which mitigate negative impacts of these features, but little is known about how oocytes set up the chromosome segregation machinery. Defining the oocyte-specific mechanisms would be crucial to understand error-prone chromosome segregation in human oocytes. Furthermore, it may provide an insight into whether and how cancer cells might gain resistance to anti-mitotic drugs by activating these pathways.
To understand the molecular pathways which set up the chromosome segregation machinery in oocytes, we take advantage of Drosophila oocytes as a "discovery platform" because of their similarity to mammalian oocytes and suitability for a genetics-led mechanistic analysis. In Drosophila oocytes, as in human oocytes, meiotic chromosomes form a compact cluster called the karyosome within the nucleus. Later, meiotic chromosomes assemble a bipolar spindle without centrosomes in the large volume of the cytoplasm, and establish bipolar attachment. We have identified genes/proteins and regulations specifically important for chromosome organisation and/or spindle formation in oocytes.
The synaptonemal complex assembles during meiotic prophase I and assists faithful exchanges between homologous chromosomes, but how its assembly/ disassembly is regulated remains to be understood. We showed how two major post-translational modifications, phosphorylation and ubiquitination, cooperate to promote synaptonemal complex assembly. We found that the ubiquitin ligase complex SCF is important for assembly and maintenance of the synaptonemal complex in female meiosis. This function of SCF is mediated by two substrate-recognizing F-box proteins, Slmb/βTrcp and Fbxo42. SCF-Fbxo42 down-regulates the phosphatase subunit PP2A-B56, which is important for synaptonemal complex assembly and maintenance.
Barbosa, P., Zhaunova, L., Debilio, S., Steccanella, V., Kelly, V., Ly, T., and Ohkura H. (2021) SCF-Fbxo42 promotes synaptonemal complex assembly by downregulating PP2A-B56. J. Cell Biol. 220, e202009167.
Costa, M. F. A., and Ohkura, H. (2019) The molecular architecture of the meiotic spindle is remodeled during metaphase arrest in oocytes. J. Cell Biol. 218, 2854-2864.
Romé, P., and Ohkura, H. (2018) A novel microtubule nucleation pathway for meiotic spindle assembly in oocytes. J. Cell Biol. 217, 3431-3445
SCF-Fbxo42 promotes synaptonemal complex assembly by downregulating PP2A-B56.
A. Two substrate-recognition subunits of SCF, Slmb/ βTrcp and Fbxo42, are required for synaptonemal complex assembly
B. Fbxo42 co-immunoprecipitates with PP2A and 14-3-3 in addition to SCF subunits
C. Fbxo42 downregulates the PP2A-B56 subunit Wrd
D. A schematic model showing that SCF-Fbxo42 down-regulates PP2A-B56 to tip the balance of phosphorylation towards synaptonemal complex assembly. Barbosa et al (2021).