减数分裂I期纺锤体动力学的分子调控机制

During meiosis, DNA duplicates once and is segregated into gametes through two consecutive cell divisions. This makes the gametes become haploid and allows fertilized cells to return to a diploid state. The spindle is responsible for chromosome segregation with its microtubules attached to the kinetochores on the chromosomes. Unlike mitotic kinetochores which are organized in a bi-orientation configuration, kinetochores on the sister chromosomes are mono-oriented during meiosis I, while homologous chromosomes pair and form chiasmata. Mono-oriented sister kinetochores and chiasmata may then contribute to the unique spindle dynamics as discovered in our recent preliminary study. Intriguingly, the meiotic spindle appears to elongate faster and reach a longer metaphase length than the mitotic spindle during preanaphase I . In addition, we have identified the minus –end directed kinesin klp2p as a key player in regulating meiotic spindle dynamics. Based on this preliminary data, we proposed that meiotic I spindle dynamics may be regulated by yet unknown mechanisms involved klp2p and/or other key spindle regulatory proteins such as ase1p and cut7p. In this proposal, we will employ a combination of live-cell microscopy, yeast genetics and biochemical approaches to uncover the molecular mechanisms underlying meiotic spindle dynamics. As meiosis is essential for sexual reproduction, our work will facilitate the further development of reproductive biology.

减数分裂将单次复制的DNA遗传物质经连续的两次细胞分裂分配形成单倍体配子，进而确保后续生殖发育过程细胞染色体数目的稳定。纺锤体通过微管与染色体上的动点连接，介导染色体的准确分配。减数分裂I期姐妹染色体上的动点形成单极定向而非有丝分裂的双极定向，同时同源染色体发生交叉。这些特异的结构使减数分裂I期纺锤体动力学亦发生相应变化，其过程可能由特异的分子机制调控。人们对减数分裂I期纺锤体动力学调控的研究仍然不多、理解不足。我们初步的研究不仅揭示了减数分裂I期纺锤体延伸较快、达到中期的长度更长等特点，而且鉴定出了调控减数分裂I期纺锤体动力学的特异驱动蛋白klp2p。因此，我们拟综合利用高分辨荧光活细胞显微镜观察技术，酵母遗传学及生物化学手段，系统研究减数分裂I期纺锤体动力学的分子调控机理。由于减数分裂与生殖健康紧密相关，因此本研究将为生殖医学研究奠定坚实的理论基础。

减数分裂确保准确形成单倍体配子，是生殖健康的重要保障。人们对减数分裂与有丝分裂相似细胞生物学过程的分子调控差异仍然理解不深。因此两种不同细胞分裂形式的关键分子调控事件是细胞生物学领域备受关注的课题。本项目重点利用高分辨率活细胞显微镜观察技术并结合细胞生物学、分子生物学和酵母遗传学技术手段，着重研究减数分裂I期纺锤体动态调控的分子机制。研究结果揭示进化上保守的驱动蛋白14家族蛋白Klp2协同微管绑捆蛋白Ase1特异维系减数分裂纺锤体稳定，为深入理解有丝分裂和减数分裂不同调控机制奠定了基础；揭示了同源染色体交叉互换结构在减数分裂纺锤体动态调控方面具有重要作用，为深入解析有丝分裂和减数分裂纺锤体动态差异提供了新的研究视角；阐明了微管壁及核膜上非中心体微管生成的分子机制，为研究非中心体微管形成提供了新的观点。项目执行期间，共发表通讯作者论文7篇。本项目研究成果使人们认识到有丝和减数两种细胞分裂形式的纺锤体动态调控存在差异，将推动人们在分子层面深入理解这些差异的调控机理并推动理解有丝和减数两种细胞分裂形式中染色体不同分配和分离的分子基础。