Septins define a novel type of cytoskeletal proteins that are conserved from yeast to humans. Septins form rod-shaped heterooligomeric complexes that polymerize end-to-end into filaments, which are further organized into higher-order structures such as rings, hourglasses, and gauzes. These structures act as a cellular scaffold and/or diffusion barrier to impact diverse cellular functions including cytokinesis, mitosis, cell polarization, cell migration, ciliogenesis, dendritic spine morphogenesis, and spermiogenesis. Mutations in septin genes cause hereditary neuropathy and infertility in humans. Septins are also implicated in tumorigenesis and neurodegenerative diseases such as Alzheimer's and Parkinson's. Thus, understanding septin structure and function is critically important not only for basic science but also for public health. Septins were first discovered in the budding yeast Saccharomyces cerevisiae for their essential role in cytokinesis. Since then, this organism has become the leading model for structure-function analysis of this family of proteins. In budding yeast, septins form an hourglass at the cell division site before cytokinesis, which is converted into a double ring at the onset of cytokinesis. The hourglass acts as a scaffold for actomyosin ring (AMR) assembly and also as a diffusion barrier to restrict cell growth to the daughter cell compartment, whereas the double ring sandwiches the AMR and acts as a diffusion barrier to restrict diffusible factors to the division site during cytokinesis. We have pioneered the analysis of native septin structures and dynamics during the cell cycle using cutting-edge technologies including platinum-replica electron microscopy (PREM), FRAP, photo-activation, photo-conversion, and super-resolution 3D-SIM. In this application, we propose to define the mechanism and function for the regulation of septin high-order assembly by septin-associated kinases (Aim 1). We will also establish the mechanism and function for sumoylation, phosphatase, and anillin-controlled septin reorganization during the cell cycle (Aim 2). The insights gained from our proposed studies will help understand the assembly, regulation, and function of this exciting cytoskeleton in other systems.

Public Health Relevance

Septins are conserved cytoskeletal proteins that form distinct high-order structures for the execution of their scaffolding and/or diffusion-barrier roles in diverse cellular functions such as cytokinesis, cell polarization, dendritic spine morphogenesis, and spermiogenesis. Defects in septins are associated with cancer, neurodegenerative diseases, and infertility. Thus, our proposed study on the regulation of septin high-order assembly and the dynamic remodeling of septin architecture is fundamentally important not only for basic research but also for public health.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
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Gindhart, Joseph G
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University of Pennsylvania
Anatomy/Cell Biology
Schools of Medicine
United States
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Marquardt, Joseph; Chen, Xi; Bi, Erfei (2018) Architecture, remodeling, and functions of the septin cytoskeleton. Cytoskeleton (Hoboken) :