Dr. Yin Loon Lee from the A*Star Institute in Singapore is visiting Ithaca next week and will give a talk on “Nucleus-cytoskeleton coupling in development and disease“. The seminar will take place next Thursday (October 23), at 1pm, in 224 Weill Hall.

Talk abstract

Tissues throughout the body experience constant mechanical stress – muscles contract, lungs expand during respiration, and the skin gets abraded. At the cellular level, beyond housing the genome, the nucleus also functions as a mechanotransduction hub, in part through the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. LINC complexes consist of inner nuclear membrane SUN proteins that bind outer nuclear membrane KASH proteins in the perinuclear space. SUN proteins interact with the nuclear lamina, including lamin A/C (LMNA), and KASH proteins interact with the cytoskeleton, enabling the LINC complex to mechanically couple the nucleus to the cytoskeleton and the extracellular environment.

The combinatorial interaction of two SUN and six KASH proteins lead to more than a dozen different LINC complexes, with alternative splicing further expanding their diversity. We examined the striated muscle-specific Nesprin-1α isoform. Using proximity labelling proteomic and genetic approaches, we identified a role for Nesprin-1α in recruiting microtubule-organizing centers (MTOCs) to the muscle nuclear envelope via Akap450, a process important for nuclear positioning in myotubes. In mouse models of LMNA-associated muscular dystrophy and cardiomyopathy, disruption of Nesprin-1 interaction with SUN proteins ameliorated pathology and prevented MTOC and microtubule-associated protein recruitment to the nuclear envelope in myotubes and cardiomyocytes, suggesting that microtubule-based forces drive disease progression. Importantly, adeno-associated virus delivery of a LINC-disrupting transgene to the heart improved outcomes even after cardiomyopathy disease onset, pointing to a potential therapeutic strategy for LMNA cardiomyopathy.

By focusing on a specific role of LINC complexes, we were able to elucidate novel biology and understand pathology in a mechanosensitive disease. We hope to extend this approach to other LINC complexes and other mechanosensitive diseases.

Biography

Yin Loon Lee ’03, pursued undergraduate research in microtubule cell biology at Cornell University with Tim Huffaker. After returning to his native Singapore for a few years, he moved back to the U.S. for a PhD at Stanford University with Tim Stearns on the nanoscale architecture and function of centriole proteins involved in cilia formation. At Stanford, he collaborated with W.E. Moerner’s lab to use Stimulated Emission Depletion (STED) super-resolution microscopy to characterize the nine-fold symmetric organization of centriole proteins in multi-ciliated tracheal epithelial cells. Yin Loon then joined Brian Burke’s laboratory at the Institute of Medical Biology in A*STAR, Singapore, to unravel the role of the Linker of Nucleoskeleton and Cytoskeleton complex in a variety of cellular, developmental and disease contexts. With Brian, Colin Stewart, and others, Yin Loon co-founded Nuevocor, a spinoff biotech company that in-licensed A*STAR technology to develop a cardiac gene therapy for LMNA dilated cardiomyopathy. Currently, Yin Loon’s research group in the A*STAR Skin Research Labs focuses on the role of nuclear mechanotransduction in homeostasis and disease, in skin and other organs.