Cellular rejuvenation during oogenesis

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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.