In vivo analysis of nuclear mechanics and mechanotransduction

Daniel Starr and GW Gant Luxton are studying a protein complex known as LINC, whose role is to physically connect the nucleus to the cell’s interior scaffolding system, otherwise known as the cytoskeleton. The LINC complex is involved in translating mechanical forces inside the cell into chemical signals, but how that translation happens and how it is regulated remains unknown. In many diseases, including cancer, heart disease, muscular dystrophy and neurodegenerative disorders, cells lose the ability to correctly translate these cues. Starr and Luxton are leading a team to study how LINC complexes are formed in the cell, how they organize and influence structures within the nuclei known as nucleoli, and how they regulate the cell’s mechanical properties.  

Affiliated Investigators

G.W. Gant Luxton, Ph.D.

University of California, Davis

G.W. Gant Luxton is an Associate Professional Researcher/Principal Investigator of Molecular and Cellular Biology at the University of California, Davis. His laboratory investigates the role of the nucleus during mechanotransduction, or the fundamental ability of cells to sense and respond to mechanical forces. Their lens on nuclear mechanotransduction is the conserved nuclear envelope-spanning molecular bridge known as the linker of nucleoskeleton and cytoskeleton (LINC) complex, which mechanically integrates the nucleus with the cytoskeleton and consequently the extracellular environment. They use a suite of cutting-edge biophysical, cell biological, quantitative imaging, and synthetic biological approaches to investigate the assembly of functional LINC complexes as well as how LINC complex dysfunction contributes to human neuromuscular disease pathogenesis.  

Dr. Luxton was trained as a virologist in the laboratory of Dr. Gregory A. Smith at Northwestern University Feinberg School of Medicine. During his graduate career, Dr. Luxton revealed novel mechanistic insights into alpha-herpesvirus neuroinvasion by identifying the viral tegument protein pUL36 as the key mediator of microtubule-dependent capsid transport in infected neurons and non-neuronal cells. Next, Dr. Luxton joined the laboratory of Dr. Gregg G. Gundersen at Columbia University Irving Medical Center as a postdoctoral fellow. There, Dr. Luxton helped establish rearward nuclear movement during centrosome orientation in wounded fibroblast monolayers as the premiere assay for investigating the mechanisms of nuclear-cytoskeletal coupling by LINC complexes as well as the impact of genetic mutations in nuclear envelope proteins associated with human diseases (i.e. nuclear laminopathies) on LINC complex function. Dr. Luxton’s research lead to the discovery of transmembrane actin-associated nuclear (TAN) lines, which are linear arrays of LINC complexes composed of the KASH protein nesprin-2G and the SUN protein SUN2 that harness the forces generated by the retrograde flow of perinuclear actin cables to move the nucleus rearward during centrosome orientation in fibroblasts polarizing for migration. 

In 2011, Dr. Luxton established his research group at the University of Minnesota-Twin Cities. In 2016, he was named a HHMI Faculty Fellow for Inclusive Excellence in 2016. In 2018, he was named a Whitman Center Early Career Fellow by the Marine Biological Laboratory as well as a Scialog Fellow by the Research Corporation for Science Advancement and the Gordon and Betty Moore Foundation. In 2020, Dr. Luxton moved his research group to the Department of Molecular and Cellular Biology at the University of California, Davis.

Daniel Starr, Ph.D.

University of California, Davis

Daniel Starr is a professor of Molecular and Cellular Biology at the University of California, Davis. His laboratory studies how nuclei move, and then anchor to, a specific part of a cell throughout development. The Starr Lab focuses on the molecular mechanisms of KASH and SUN proteins in the nuclear envelope to determine how the nucleus connects to the cytoskeleton, primarily using C. elegans as a model system to better understand nuclear positioning in a developmental context. The lab team answers fundamental questions in cell and developmental biology, including how motors target to the nuclear envelope and how the activities of motors are switched throughout development, how the nuclear lamina is connected to the nuclear envelope, how actin filaments move nuclei, and how molecular forces are transferred across the nuclear envelope. All of these mechanisms have been shown to be conserved across eukaryotes and defects in these processes lead to a variety of neuromuscular diseases. The Starr Lab is particularly interested in how these mechanisms are regulated to squeeze nuclei through constricted spaces and how this relates to development and cancer metastasis.

Dr. Starr was trained as a developmental geneticist in the laboratory of Dr. Michael Goldberg at Cornell University, where he characterized a complex of kinetochore proteins, showed they were conserved across eukaryotes, and found that they function to recruit the microtubule motor dynein to the kinetochore to move chromosomes. Starr then joined Min Han’s group with the Howard Hughes Medical Institute at the University of Colorado, Boulder. There he and his colleagues used forward genetics in C. elegans to discover KASH proteins and propose the LINC complex model where KASH and SUN proteins span the nuclear envelope and connect the nucleus to the cytoskeleton.  

In 2003, Starr established his research group at UC Davis. He was named a Basil O’Conner Scholar by the March of Dimes in 2005, which supports early-career scientists embarking on independent research careers to study health issues of mothers and babies. Starr also is the director of the PREP@UC Davis training program, and serves as a deputy editor for Science Advances.