Research Interests
Nuclear Envelope Dynamics in Meiotic Quality Control and Oocyte Development
The overall goal of my research program is to uncover the mechanisms of quality control during meiosis. Meiosis is a dynamic cell cycle program that transmits genetic information from one generation to the next during sexual reproduction. Errors in meiosis can have severe consequences, including incorrect chromosome numbers in egg cells underlying birth defects such as Down syndrome. Thus, defective meiotic cells must be eliminated as part of a quality control process. Recent breakthroughs suggest that the nuclear envelope of meiotic cells plays a key role in this process. Focusing on the oocytes –precursors of eggs – in the nematode Caenorhabditis elegans as a model system, we aim to elucidate how the dynamic nuclear envelope detects and responds to meiotic errors to promote quality control in developing oocytes. We will use a wide variety of experimental strategies, including high resolution live cell imaging, genetics, synthetic biology, and engineering approaches to fill this fundamental knowledge gap.
Timelapse imaging showing the nucleus of a maturing oocyte going through collapse after acute depletion of the only lamin protein in C. elegans, LMN-1, specifically in the germline. Chromosome in magenta, nuclear envelope in green.
Mechanotransduction mechanisms at the nuclear envelope during meiosis and oocyte development
Oogenesis involves transduction of mechanical forces from the cytoskeleton to the nuclear envelope. In Caenorhabditis elegans, oocyte nuclei lacking the single lamin protein LMN-1 are vulnerable to collapse under forces mediated through LINC (linker of nucleoskeleton and cytoskeleton) complexes. Early on during my postdoc, I investigated the force-balance at the oocyte nuclear envelope and found that acute disruption of oocyte nuclear lamina leads to nuclear collapse and the loss of maturing oocytes. By collaborating with Dr. Lydia Sohn’s lab in the Department of Mechanical Engineering at UC Berkeley, we measured nuclear stiffness using microfluidics and demonstrated that the nuclear lamina collaborates with other nuclear envelope proteins to confer resilience to maturing oocyte nuclei against external mechanical stress. This work demonstrates that unbalanced force at the nuclear envelope can jeopardize fertility by crushing oocyte nucleus and elucidates the molecular mechanisms preventing that from happening. More details about this work can be found here.
A Piezo-dependent meiotic checkpoint at the oocyte nuclear envelope
Sexual reproduction relies on robust quality control during meiosis. Assembly of the synaptonemal complex between homologous chromosomes (synapsis) regulates meiotic recombination and is crucial for accurate chromosome segregation in most eukaryotes. Synapsis defects can trigger cell cycle delays and, in some cases, apoptosis (the "synapsis checkpoint"). In C. elegans, this checkpoint requires chromosome Pairing Centers (PCs) that attach to the nuclear envelope. However, how PCs help meiotic cells detect and respond to synapsis defects remained unclear. Work by many labs show that the kinase PLK-2 relocates from PCs to synapsed chromosomes after synapsis completes, and sticks around at PCs when synapsis fails. However, testing if PLK-2 at PCs triggers apoptosis remained tricky, as one would need to make PLK-2 stay at PCs even after synapsis. We developed and deployed a chemically induced proximity (CIP) system to manipulate PLK-2’s subcellular localization in vivo. By keeping PLK-2 at the PCs, we demonstrated that persistence of the polo-like kinase PLK-2 at PCs induced apoptosis of oocytes, mediated by phosphorylation and destabilization of the nuclear lamina. Unexpectedly, we found that the mechanosensitive ion channel Piezo1/PEZO-1, which typically localizes to the plasma membrane, also localized to the nuclear envelope and was required to transduce this signal to promote apoptosis in maturing oocytes. More details can be found here.
Top: how we repurposed the auxin-inducible degradation (AID) system into a chemically induced proximity (CIP) system. Point mutations in the F-box protein TIR1 prevent the assembly of the E3 ligase, converting the AID system to a dimerization tool. This enables conditional relocalization of proteins in live animals. Bottom: timelapse live cell imaging showing the dynamics of the oocyte nuclear envelope (labeled by SUN-1::mRuby) without or with synapsis checkpoint activation using CIP.
Working model of a Piezo-dependent checkpoint mechanism monitoring oocyte quality at the nuclear envelope to eliminate defective oocytes. Pairing, synapsis, and recombination between homologous chromosomes are essential for accurate meiotic chromosome segregation. In C. elegans, failures in chromosome synapsis promote apoptosis of affected oocytes. Following synapsis defects, PLK-2 persists at the pairing centers (1). This phosphorylates the nuclear lamin protein LMN-1 and destabilizes the NE (2), which triggers PEZO-1-dependent apoptosis (3).
Together, our findings provide direct evidence of a mechanosensitive ion channel in detecting/responding to events originating in the oocyte nucleus. This suggests a new surveillance mechanism and together with my previous work on nuclear envelope mechanotransduction, sets up the stage for exploring how the dynamic nuclear envelope promotes meiotic quality control and balance the needs of both quality and quantity during oocyte development. Questions we seek to address in our lab include (1) How do Piezo channels promote meiotic quality control? (2) How do mechanotransduction pathways at the nuclear envelope coordinate both quality and quantity during oocyte development? and (3) How does nuclear envelope-based meiotic quality control evolve across diverse species? With 1 in 6 adults worldwide facing infertility – women disproportionately due to the sharp decline of oocyte quality with age, our work could advance mechanistic understanding of oocyte quality control during reproductive aging and inform strategies to improve human reproductive health.