Biology subjects

Hanson, S. M.

Publications and source records attributed to Hanson, S. M..

22 records · Page 2Linked to original sources

bioRxiv2023

A developmentally defined population of neurons in the lateral septum controls responses to aversive stimuli

When interacting with their environment, animals must balance exploratory and defensive behavior to evaluate and respond to potential threats. The lateral septum (LS) is a structure in the ventral forebrain that calibrates the magnitude of behavioral responses to stress-related external stimuli, including the regulation of threat avoidance. The complex connectivity between the LS and other parts of the brain, together with its largely unexplored neuronal diversity, makes it difficult to understand how defined LS circuits control specific behaviors. Here, we describe a mouse model where the deletion of the transcriptional regulator Prdm16 in cells with a common developmental origin (Nkx2.1-lineage) results in the almost complete ablation of neurons from this lineage in the LS. Using a combination of single-nucleus RNA sequencing, histological and electrophysiological methods and behavioral analyses, we discovered that Crhr2-expresssing neurons are specifically affected in mutant mice, resulting in connectivity and electrophyisiological defects. This neuronal population is specifically activated in stressful contexts, and its removal results in increased exploratory behavior, even under stressful conditions. Our study extends the current knowledge about how defined neuronal populations within the LS can evaluate contextual information to select appropriate behavioral responses. This is a necessary step towards understanding the crucial role that the LS plays in neuropsychiatric conditions where defensive behavior is dysregulated, such as anxiety and aggression disorders.

neuroscience↗

bioRxiv2023

Extracting thermodynamic properties from van 't Hoff plots with emphasis on temperature-sensing ion channels

Transient receptor potential (TRP) ion channels are among the most well-studied classes of temperature-sensing molecules. Yet, the molecular mechanism and thermodynamic basis for the temperature sensitivity of TRP channels remains to this day poorly understood. One hypothesis is that the temperature-sensing mechanism can simply be described by a difference in heat capacity between the closed and open channel states. While such a two-state model may be simplistic it nonetheless has descriptive value, in the sense that it can be used to to compare overall temperature sensitivity between different channels and mutants. Here, we introduce a mathematical framework based on the two-state model to reliably extract temperature-dependent thermodynamic potentials and heat capacities from measurements of equilibrium constants at different temperatures. Our framework is implemented in an open-source data analysis package that provides a straightforward way to fit both linear and nonlinear van t Hoff plots, thus avoiding some of the previous, potentially erroneous, assumptions when extracting thermodynamic variables from TRP channel electrophysiology data.

biophysics↗

bioRxiv2023

Molecular basis of polyglutamine-modulated ELF3 phase change in Arabidopsis temperature response

The evening complex (EC) is a tripartite DNA repressor and a core component of the circadian clock that provides a mechanism for temperature-responsive growth and development of many plants. ELF3, a component of the EC, is a disordered scaffolding protein that blocks transcription of growth genes at low temperature. At increased temperature EC DNA binding is disrupted and ELF3 is sequestered in a reversible nuclear condensate, allowing transcription and growth to proceed. The condensation is driven by a low complexity prion-like domain (PrD), and the sensitivity of the temperature response is modulated by the length of a variable polyQ tract, with a longer polyQ tract corresponding to enhanced condensate formation and hypocotyl growth at increased temperature. Here, a series of computational studies provides evidence that polyQ tracts promote formation of temperature-sensitive helices in flanking residues with potential impacts for EC stability under increasing temperature. REST2 simulations uncover a heat-induced population of condensation-prone conformations that results from the exposure of sticky aromatic residues by temperature-responsive breaking of long-range contacts. Coarse-grained Martini simulations reveal both polyQ tract length and sequence context modulate the temperature dependence of cluster formation. Understanding the molecular mechanism underlying the ELF3-PrD temperature response in plants has implications for technologies including modular temperature-response elements for heat-responsive protein design and agricultural advances to enable optimization of crop yields and allow plants to thrive in increasingly inhospitable environments.

biophysics↗

bioRxiv2017

A dynamic mechanism for allosteric activation of Aurora kinase A by activation loop phosphorylation

Many eukaryotic protein kinases are activated by phosphorylation on a specific conserved residue in the regulatory activation loop, a post-translational modification thought to stabilize the active DFG-In state of the catalytic domain. Here we use a battery of spectroscopic methods that track different catalytic elements of the kinase domain to show that the ~100-fold activation of the mitotic kinase Aurora A (AurA) by phosphorylation occurs without a population shift to the DFG-In state, and that the activation loop of the activated kinase remains highly dynamic. Instead, molecular dynamics simulations and electron paramagnetic resonance experiments show that phosphorylation profoundly alters the structure and dynamics of the DFG-In subpopulation, leading to activation of the kinase. Kinetics experiments tracking structural transitions during nucleotide binding suggest that a substantial DFG-Out subpopulation is an important feature of activated AurA that evolved to optimize the kinetics of substrate binding and product release.

biophysics↗