Nuclear Envelope Dynamics in Meiotic Quality Control - Successful sexual reproduction relies on gametes, like sperm and eggs, having exactly half the genome of their somatic progenitor cells. This is accomplished through meiosis, a cell division process that accurately segregates the two copies of homologous chromosomes inherited from both parents. During meiosis, homologous chromosomes must pair up along their lengths to enable genetic crossover, which is essential for accurate segregation. Physical pairing between homologs is usually stabilized by synapsis, where a protein complex called the synaptonemal complex (SC) assembles between homologs along their lengths. Failure in synapsis can lead to chromosome missegregation and aneuploidy, a major cause of birth defects such as Down Syndrome. In diverse organisms, defects in synapsis can trigger apoptosis to eliminate the affected meiotic cells as a quality control measure. However, the mechanisms by which meiotic cells detect and respond to synapsis failure remain unclear. My research program will address this fundamental gap using the highly tractable Caenorhabditis elegans germline as a model system. In C. elegans, defects in synapsis during meiosis promote apoptosis of oocytes – precursors of egg cells. Recently, we discovered a critical role of the oocyte nuclear envelope (NE) in apoptosis when synapsis fails. By developing and deploying a new chemically induced proximity (CIP) tool, we discovered that following synapsis failure, the Polo-like kinase PLK-2 is recruited to the oocyte NE to phosphorylate and destabilize the nuclear lamina. Unexpectedly, we found that the mechanosensitive ion channel Piezo, which typically functions at the plasma membrane, also localizes to the oocyte NE and is required to transduce this signal to promote apoptosis. This is the first evidence of mechanosensitive ion channels in transducing a signal that originates in the cell nucleus. Now, by combining cell biology, genetics, engineering, and other approaches, my lab will elucidate how the dynamic NE integrates mechanical and chemical signals to regulate quality control in developing oocytes, focusing on three distinct but complementary projects. First, we will determine the mechanisms by which Piezo channels function at the NE. Second, we will interrogate how different signaling pathways are coordinated at the NE to regulate oocyte development, leveraging our recent understanding of the mechanics of meiotic nuclei. Third, we will explore the evolutionary conservation and divergence of NE-based meiotic quality control using Pristionchus pacificus, a nematode with meiosis more similar to mammals than C. elegans. By studying nematode meiosis as a model, the questions we seek to address are at the nexus of basic cell biology, genetics, and development. As PIEZO2 is enriched in human oocyte-containing follicles, we expect that our research will uncover conserved, fundamental principles underlying the accurate transmission of genetic material during sexual reproduction. Our findings will also impact a wide range of cell biology problems related to nuclear envelope dynamics. Additionally, new tools we develop will be broadly applicable to probe diverse cellular processes in vivo.
