Cellular rejuvenation during oogenesis

核孔复合体（NPC）的功能障碍与衰老和神经退行性变广泛相关 例如ALS和阿尔茨海默病。NPC是一种大的核镶嵌蛋白 由约30个核孔蛋白（Nups）组成的复合物，调节核质交换以及 基因组功能许多NUP表现出异常缓慢的周转，因此随着年龄的增长而积累损害， 被认为有助于与年龄相关的NPC功能障碍和细胞健康的丧失。最近的研究表明 有缺陷的NPC和急性应激通过酵母中的自噬诱导NPC再循环，但这种机制是否 发生在后生动物和其生理相关性是未知的。受损的细胞机制会导致 有机体功能障碍和衰老，但无论父母的年龄，配子，如卵母细胞和 精子，确保下一代以未受损的成分重新开始。我们的实验室调查了 生殖系干细胞（GSC）分化为卵母细胞的潜在机制，卵母细胞是女性唯一的细胞， 有助于下一代和对抗衰老，以及NPC的生理作用。自噬似乎 在果蝇GSC分化过程中具有活性，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过渡所需的途径， 是卵母细胞规格和维护所必需的。我们证明了早期卵子发生基因是沉默的， 在这一转变过程中，通过涉及异染色质和NPC的机制，异染色质的形成 在卵子发生中期触发大多数NUP的上调。我们的初步结果表明，NPC经历了 在卵子发生的这一关键窗口期间广泛去除，这与Nups的转录诱导重叠。 此外，我们发现自噬因子Atg 8可以在生殖细胞到母体的过程中靶向NPC， Atg8的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一个细胞周期的基础。 在卵母细胞特化过程中进行"NPC复壮"程序，以确保卵母细胞的活力和后代适应性。我们计划 为了解决这一假设，有以下三个具体目标：1）定义NPC的时空动力学 生殖细胞向母体过渡期间的周转; 2）确定促进NPC年轻化的因素 在生殖细胞向母体过渡期间;和3）确定NPC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 部分通过推动发展调节NPC复兴计划，包括协调 通过自噬清除旧的NPC和通过异染色质形成依赖性合成新的NPC 转录。我们预计我们的研究将揭示发育生物学的新概念， 药物和衰老

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.