研究概述 Research Description
女性生殖健康是当今社会面临人口老化的重要焦点之一。卵子和胚胎发育异常是造成女性不育、流产或唐氏综合症等遗传疾病的主要成因。过往我们在卵母细胞发育成卵子的减数分裂过程中取得了多项开创性的发现，包括哺乳动物卵母细胞组装纺锤体的生物物理机制和人类卵母细胞组装不稳定的纺锤体从而错误地分离染色体的分子机制。
第一，我们发现了哺乳动物卵母细胞利用中心体蛋白组装无中心体纺锤体的机制（So and Seres et al.Science2019）。哺乳动物卵母细胞在无中心体的前提下依然表达了多个中心体蛋白。这些中心体蛋白透过一个名为液液相分离的生物物理现象，在减数分裂的过程中形成了过往未被报导过的液状纺锤体结构域。液状纺锤体结构域在纺锤体微管附近收纳并调动微管调控因子，从而在无中心体下促进纺锤体组装。
第二，我们揭示了人类卵母细胞纺锤极组装和不稳定性的机制（So et al.Science2022）。在无中心体的前提下，人类和其他哺乳动物的卵母细胞同样透过NUMA招募动力蛋白到微管负端来聚焦纺锤极。然而，除了人类以外，其他哺乳动物的卵母细胞并没有组装不稳定的纺锤体。利用反向遗传学筛选，我们鉴定出纺锤体稳定性取决于一个名为KIFC1的负端定向驱动蛋白。哺乳动物的卵母细胞大多高度表达KIFC1，唯独人类卵母细胞缺乏KIFC1。通过引入外源的KIFC1蛋白，我们成功的提高了人类卵母细胞组装纺锤体和分离染色体的准确性，首次为防治卵子染色体数目异常带来了可能。
未来我们实验室会继续利用不同的哺乳动物模型，结合国际领先的光电镜（如光片活细胞成像，扩展成像、组织透明化成像、大体积电镜）、功能丧失(如Trim-Away；Clift and So et al.Nat. Protoc.2018)、生物物理（如力生物学测量、建模）等技术，探索卵子和胚胎发育的机制。我们的研究成果将为女性不育的成因和防治提供新方向，并改善现有的医学辅助生殖技术。
Focusing on female reproductive health is a key way of dealing with population aging. Abnormal egg and embryo development are the leading causes of female infertility, miscarriage and genetic disorders such as Down Syndrome. Previously we have made several pioneering discoveries of the mechanisms underlying meiotic maturation of oocytes into eggs, such as the biophysical mechanism underlying spindle assembly in mammalian oocytes and the molecular mechanism underlying spindle instability and chromosome missegregation in human oocytes.
First, we discovered how mammalian oocytes utilize centrosomal proteins to assemble acentrosomal spindles (So and Seres et al.Science2019). Mammalian oocytes express many centrosomal proteins despite the absence of centrosomes. During female meiosis, some of these proteins undergo a biophysical phenomenon known as liquid-liquid phase separation to form a previously undescribed domain, which we termed the liquid-like meiotic spindle domain (LISD). The LISD sequesters and mobilizes centrosomal proteins with microtubule regulatory functions in proximity to spindle microtubules, thus promoting spindle assembly in the absence of centrosomes.
Second, we uncovered how are spindle poles organized and why are they unstable in human oocytes (So et al.Science2022). Human and other mammalian oocytes similarly utilize NUMA to recruit dynein to microtubule minus-ends for the focusing of acentrosomal spindle poles. However, unlike human oocytes, other mammalian oocytes do not assemble unstable spindles. Using a reverse genetic screen, we identified the minus-end-directed kinesin KIFC1 as a key determinant of meiotic spindle stability. While KIFC1 is readily expressed in most mammalian oocytes, it is deficient in human oocytes. By introducing exogenous KIFC1, we successfully increased the fidelity of spindle assembly and chromosome segregation in human oocytes. For the first time, we proposed a potential therapeutic method for reducing the risk of aneuploidy in human eggs.
With our expertise in cutting-edge light and electron microscopy and the support from the 13 core facilities at NIBS, we will continue adopting a cross-disciplinary approach to illuminate novel cellular, molecular and biophysical mechanisms underlying egg and embryo development across different mammalian models.. Our findings will provide novel insights into the causes and treatments of female infertility, and improve the existing assisted reproductive technologies.
发表文章 Publications
(*Equal contribution)
10.So, C., Menelaou, M., Uraji, J., Harasimov, K., Steyer, A.M., Seres, K.B., Bucevičius, J., Lukinavičius, G., Möbius, W., Sibold, C., Tandler-Schneider, A., Eckel, H., Moltrecht, R., Blayney, M., Elder, K., Schuh, M. “Mechanism of spindle pole organization and instability in human oocytes” Science (2022); Feb; 375(6581):eabj3944
- Covered by Nat. Cell Biol. in “Spindle instability in human oocytes”
- Highlighted by J. Assist. Reprod. Genet. in “Failure to focus seems to be a hominid thing”
9.So, C.*, Cheng, S.*, Schuh, M. “Phase separation during germline development” Trends Cell Biol. (2021); Apr; 31(4):254-268
8. Chan, Y.W.*,So, C.*, Yau, K.L., Chiu, K.C., Wang, X., Chan, F.L., Tsang, S.Y. “Adipose-derived stem cells and cancer cells fuse to generate cancer stem cell-like cells with increased tumorigenicity” J. Cell Physiol. (2020); Oct; 235(10):6794-6807
7.So, C.*, Seres, K.B.*, Steyer, A.M., Mönnich, E., Clift, D., Pejkovska, A., Möbius, W., Schuh, M. “A liquid-like spindle domain promotes acentrosomal spindle assembly in mammalian oocytes” Science (2019); Jun; 364(6447):eaat9557
- Recommended by F1000Prime
- Highlighted by J. Assist. Reprod. Genet. in “Phase transitions in human ARTs: fertility preservation comes of age”
6. Xu, Y.,So, C., Lam, H.M., Fung, M.C., Tsang, S.Y. “Flow cytometric detection of newly-formed breast cancer stem cell-like cells after apoptosis reversal” J. Vis. Exp. (2019); Jan; (143)
5. Clift, D.*,So, C.*, McEwan, W.A., James, L.C., Schuh, M. “Acute and rapid degradation of endogenous proteins by Trim-Away” Nat. Protoc. (2018); Oct; 13(10):2149-2175
4. Xu, Y.,So, C., Lam, H.M., Fung, M.C., Tsang, S.Y. “Apoptosis reversal promotes cancer stem cell-like cell formation” Neoplasia (2018); Mar; 20(3):295-303
3. Yang, H., Buisson, S., Bossi, G., Wallace, Z., Hancock, G.,So, C., Asfield, R., Vuidepot, A., Mahon, T., Molloy, P., Oates, J., Paston, S.J., Aleksic, M., Hassan, N.J., Jakobsen, B.K., Dorrell, L. “Elimination of latently HIV-infected cells from antiretroviral therapy-suppressed subjects by engineered immune-mobilizing T-cell receptors” Mol. Ther. (2016); Nov; 24(11):1913-1925
2. Lo, I.C., Chan, H.C., Qi, Z., Ng, K.L.,So, C., Tsang, S.Y. “TRPV3 channel negatively regulates cell cycle progression and safeguards the pluripotency of embryonic stem cells” J. Cell Physiol. (2016); Feb; 231(2):403-413
1. Qi, Y., Qi, Z., Li, Z., Wong, C.K.,So, C., Lo, I.C., Huang, Y., Yao, X., Tsang, S.Y. “Role of TRPV1 in the differentiation of mouse embryonic stem cells into cardiomyocytes” PLoS One (2015); Jul; 10(7):e0133211
