Interested in cell division in tissues in vivo? Curious about how the mammalian brain grows so fast and why it is so vulnerable to mutations affecting cell division? The Dwyer Lab in the Department of Cell Biology at the University of Virginia seeks a Postdoctoral Research Associate to work on exciting new projects about the genes and mechanisms underlying normal and abnormal brain development. Funded projects focus on 1) how precise regulation of cytokinetic abscission in neural stem cells affects cell fate, cilia, and signaling pathways. 2) new mouse mutants with novel brain development phenotypes. To apply please email Dr. Dwyer or message her in LinkedIn or apply at UVA's Workday web page to posting "R0032622".

The Dwyer Lab in the Department of Cell Biology at the University of Virginia seeks one or two Postdoctoral Research Associates to work on exciting new projects about the genes and mechanisms underlying normal and abnormal brain development. We have been studying the cell biology of neural development for several years, with a recent emphasis on cell division and cytoskeleton. Newly funded projects focus on 1) new mouse mutants with novel brain development phenotypes, and 2) how cytokinesis regulation in neural stem cells affect cell fate, cilia, and signaling pathways. Approaches include genetics and genomics, cell and tissue culture, lineage tracing, multiple types of microscopy, molecular biology, biochemistry, and whatever skills you may bring to the lab. Postdoctoral research associates will manage their own projects, interact with other lab members and collaborators, present their work at lab meetings and conferences, and contribute to grant applications and manuscripts for publication. Candidates will be expected to learn new techniques as a part of their training requirement. This position also includes opportunities to help mentor and teach students. The Dwyer Lab is located in renovated open lab space with a strong, collegial group of neighboring labs studying cell and developmental biology. The lab is committed to a diverse, equitable, and inclusive environment, and encourages applications from women and underrepresented groups. The position is available immediately and is supported by NIH funding. The Cell Biology Department at UVA is an excellent training environment for curious, highly motivated scientists. The University provides professional development workshops, and there are support communities on campus including the UVA Postdoc Association, and UVA Women in Medical Sciences (WIMS).

The cytoskeleton has the remarkable ability to self-organize into active materials which underlie diverse cellular processes ranging from motility to cell division. Actomyosin is a canonical example of an active material, which generates cellularscale contractility in part through the forces exerted by myosin motors on actin filaments. While the molecular players underlying actomyosin contractility have been well characterized, how cellular-scale deformation in disordered actomyosin networks emerges from filament-scale interactions is not well understood. In this talk, I’ll present work done in collaboration with Sebastian Fürthauer and Nikta Fakhri addressing this question in vivo using the meiotic surface contraction wave seen in oocytes of the bat star Patiria miniata as a model system. By perturbing actin polymerization, we find that the cellular deformation rate is a nonmonotonic function of cortical actin density peaked near the wild type density. To understand this, we develop an active fluid model coarse-grained from filament-scale interactions and find quantitative agreement with the measured data. The model makes further predictions, including the surprising prediction that deformation rate decreases with increasing motor concentration. We test these predictions through protein overexpression and find quantitative agreement. Taken together, this work is an important step for bridging the molecular and cellular length scales for cytoskeletal networks in vivo.

Chromosomes are extremely long, active polymers that are spatially organized across multiple scales to promote cellular functions, such as gene transcription and genetic inheritance. During each cell cycle, chromosomes are dramatically compacted as cells divide and dynamically reorganized into less compact, spatiotemporally patterned structures after cell division. These activities are facilitated by DNA/chromatin-binding protein motors called SMC complexes. Each of these motors can perform a unique activity known as “loop extrusion,” in which the motor binds the DNA/chromatin polymer, reels in the polymer fiber, and extrudes it as a loop. Using simulations and theory, I show how loop-extruding motors can collectively compact and spatially organize chromosomes in different scenarios. First, I show that loop-extruding complexes can generate sufficient compaction for cell division, provided that loop-extrusion satisfies stringent physical requirements. Second, while loop-extrusion alone does not uniquely spatially pattern the genome, interactions between SMC complexes and protein “boundary elements” can generate patterns that emerge in the genome after cell division. Intriguingly, these “boundary elements” are not necessarily stationary, which can generate a variety of patterns in the neighborhood of transcriptionally active genes. These predictions, along with supporting experiments, show how SMC complexes and other molecular machinery, such as RNA polymerase, can spatially organize the genome. More generally, this work demonstrates both the versatility of the loop extrusion mechanism for chromosome functional organization and how seemingly subtle microscopic effects can emerge in the spatiotemporal structure of nonequilibrium polymers.

Evidence regarding protein structure and function manifest the imperative role that dynamics play in proteins, underlining reconsideration of the unanimated sequence-to-structure-to-function paradigm. Structural dynamics portray a heterogeneous energy landscape described by conformational ensembles where each structural representation can be responsible for unique functions or enable macromolecular assemblies. Using the human p27/Cdk2/Cyclin A ternary complex as an example, we highlight the vital role of intra- and intermolecular dynamics for target recognition, binding, and inhibition as a critical modulator of cell division. Rapidly sampling configurations is critical for the population of different conformational ensembles encoding functional roles. To garner this knowledge, we present how the integration of (sub)ensemble and single-molecule fluorescence spectroscopy with molecular dynamic simulations can characterize structural dynamics linking the heterogeneous ensembles to function. The incorporation of dynamics into the sequence-to-structure-to-function paradigm promises to assist in tackling various challenges, including understanding the formation and regulation of mesoscale assemblies inside cells.

Epithelial cell sheets form a fundamental role in the developing embryo, and also in adult tissues including the gut and the cornea of the eye. Soft and active matter provides a theoretical and computational framework to understand the mechanics and dynamics of these tissues.I will start by introducing the simplest useful class of models, active brownian particles (ABPs), which incorporate uncoordinated active crawling over a substrate and mechanical interactions. Using this model, I will show how the extended ’swirly’ velocity fluctuations seen in sheets on a substrate can be understood using a simple model that couples linear elasticity with disordered activity. We are able to quantitatively match experiments using in-vitro corneal epithelial cells.Adding a different source of activity, cell division and apoptosis, to such a model leads to a novel 'self-melting' dense fluid state. Finally, I will discuss a direct application of this simple particle-based model to the steady-state spiral flow pattern on the mouse cornea.