Cellular rejuvenation during oogenesis

核孔复合体功能障碍被广泛认为与衰老和神经退行性变有关。 如肌萎缩侧索硬化症和阿尔茨海默病。核祖细胞是一种大的核膜包埋蛋白 由大约30个核孔素(NUP)组成的复合体，调节核质交换以及 基因组的功能。许多核弹表现出异常缓慢的周转，因此随着年龄的增长而积累损害，这是 被认为是与年龄相关的鼻咽癌功能障碍和细胞健康丧失的原因。最近的研究表明 有缺陷的NPC和急性应激通过自噬在酵母中诱导NPC循环，但这一机制是否 发生在后生动物中，其生理相关性尚不清楚。受损的细胞机械可能会导致 器官功能障碍和衰老，但不考虑父母的年龄，配子，如卵母细胞和 精子，确保下一代以未损坏的成分重新开始。我们的实验室正在调查 生殖系干细胞(GSCs)分化为卵母细胞的机制 这有助于下一代，并无视衰老和全国人大的生理作用。自噬现象似乎 在果蝇的GSC分化过程中表现活跃，但其生物学意义尚不完全清楚。 我们最近描述了果蝇卵子发生过程中生殖细胞向母体转化所需的途径 是卵母细胞规范和维护所必需的。我们证明了早期卵子发生基因是沉默的 在这个转变过程中，通过一种涉及异染色质和NPC的机制，以及异染色质的形成 在卵子发生中期，会触发大多数核蛋白的上调。我们的初步结果表明，鼻咽癌经历了 在这个与NUP转录诱导重叠的卵子发生的关键窗口期间，广泛的去除。 此外，我们发现，在生殖细胞到母体的过程中，一种自噬因子Atg8可以靶向于NPC。 Atg8基因转换和缺失导致生殖细胞异常和早期卵子发生的异常表达 基因。因此，我们的中心假设是选择性自噬和程序化转录是 “鼻咽癌年轻化”计划期间卵母细胞规范，以确保卵母细胞的存活率和后代健康。我们计划 为了解决这一假说，有以下三个具体目标：1)定义鼻咽癌的时空动力学 生殖细胞向母体转变过程中的周转；2)决定促进鼻咽癌年轻化的因素 在生殖细胞到母体的转变过程中；以及3)确定鼻咽癌年轻化的生物学相关性 卵子发生和生育的途径。我们希望发现生殖细胞到母体的转变会重置细胞 寿命在一定程度上是通过推动发展调节的NPC年轻化计划，包括协调 自噬清除旧的鼻咽癌细胞和异染色质依赖合成新的鼻咽癌细胞 抄写。我们预计我们的研究将发现发育生物学中的新概念，即再生 医学和衰老。

Dysfunction of the nuclear pore complex (NPC) has been extensively linked to aging and neurodegenerative conditions such as ALS and Alzheimer’s disease. NPCs are large nuclear envelope-embedded protein complexes composed of about 30 Nucleoporin (Nups) that regulate nucleocytoplasmic exchange as well as genome function. Many Nups exhibit unusually slow turnover and thus accumulate damage with age, which is thought to contribute to age-associated NPC dysfunction and loss of cellular fitness. Recent studies revealed that defective NPCs and acute stress induce NPC recycling via autophagy in yeast, but whether this mechanism occurs in metazoans and its physiological relevance are unknown. Damaged cellular machinery can lead to organismal dysfunction and aging, yet irrespective of the age of the parents, the gametes, such as oocyte and sperm, ensure that the next generation starts afresh with undamaged components. Our labs investigate the mechanisms underlying the differentiation of germline stem cells (GSCs) into oocytes, the only cells of the female that contribute to the next generation and defy aging, and physiological roles of the NPC. Autophagy appears to be active during GSC differentiation in Drosophila, but the biological significance is not completely understood. We recently described pathways required for a germ cell-to-maternal transition during Drosophila oogenesis that is required for oocyte specification and maintenance. We demonstrated that early oogenesis genes are silenced during this transition via a mechanism involving heterochromatin and NPCs, and that heterochromatin formation during mid-oogenesis triggers upregulation of most Nups. Our preliminary results suggest that NPCs undergo extensive removal during this critical window of oogenesis, which overlaps with transcriptional induction of Nups. Additionally, we found that an autophagy factor Atg8 can be targeted to NPCs during germ cell-to-maternal transition and that loss of Atg8 leads to germ cell abnormalities and aberrant expression of early oogenesis genes. Thus, our central hypothesis is that selective autophagy and programmed transcription underlie an “NPC rejuvenation” program during oocyte specification to ensure oocyte viability and progeny fitness. We plan to address this hypothesis with the following three specific aims: 1) Define the spatiotemporal dynamics of NPC turnover during the germ cell-to-maternal transition; 2) Determine the factors that promote NPC rejuvenation during the germ cell-to-maternal transition; and 3) Determine the biological relevance of NPC rejuvenation pathways to oogenesis and fertility. We expect to discover that the germ cell-to-maternal transition resets cellular lifespan in part by driving a developmentally regulated NPC rejuvenation program, involving coordinated clearance of old NPCs by autophagy and the synthesis of new NPCs via heterochromatin formation-dependent transcription. We anticipate our research will uncover new concepts in developmental biology, regenerative medicine, and aging.