Biology subjects

Thompson-Peer, K. L.

Publications and source records attributed to Thompson-Peer, K. L..

6 recordsLinked to original sources

bioRxiv2026

Opposing Roles for the Spectraplakin Short Stop in Stable and Dynamic Dendrites Reveal Divergent DLK Signaling and a Role in Dendrite Regeneration

Dendrites are vital to neuronal function, and dendrite injury occurs after neurological traumas such as stroke, traumatic brain injury, or neurodegenerative diseases. Despite their importance, the mechanisms underlying dendrite maintenance or regeneration remain poorly understood. The Drosophila gene short stop (shot), orthologous to ACF7/MACF1 in mammals, functions as an actin-microtubule crosslinker during neuronal development. Here, we investigate shot's role in dendrite stability and repair using Drosophila sensory neurons. We find that shot plays opposing, cell type-specific roles in dendrite maintenance: it restricts excessive branch growth in simple, stable neurons, while being required for dendrite coverage in complex, dynamic neurons. These opposing functions are reflected in distinct localization patterns in stable versus dynamic dendrite arbors. Loss of shot destabilizes the microtubule cytoskeleton in stable neurons, and activates Wallenda/DLK signaling in both stable and dynamic neurons. Downstream of Wallenda/DLK, JNK signaling diverges between neuron types, with canonical basket/JNK activation occurring only in neurons with stable dendritic arbors. After injury, shot promotes dendrite regeneration in both neuron types and accumulates in distinct shapes in regenerated dendrites, with specific domains critical for proper Shot accumulation patterns. Collectively, these findings establish shot as a context-dependent regulator of dendrite maintenance and repair, and demonstrate that the structural identity of a dendritic arbor shapes how neurons sense and respond to cytoskeletal perturbation.

cell biology↗

bioRxiv2026

Implementation of ddaE neuron growth mechanism in graph grammar replicates biological features

Dendrites develop branching patterns that are critical for their function, yet the mechanisms guiding arbor morphology remain incompletely understood, and quantitative models predicting how signals guide morphology remain limited. The ddaE neuron in Drosophila larvae is a proprioceptive sensory neuron with a characteristic asymmetric dendrite arbor that exhibits posterior-biased branching. We developed a computational model using Dynamical Graph Grammar (DGG) to simulate ddaE dendrite development as a graph-based dynamical system, using a single morphogen gradient to establish arbor architecture. Our simulations of ddaE dendrites, guided by the spatial gradient of the Teneurin-m (Tenm) morphogen combined with resource constraints and self-avoidance rules, accurately recapitulate the morphological features of biological ddaE neurons, including primary branch orientation, posterior bias, branch tree distributions, and branch length statistics. We find that the response to a single morphogen gradient is sufficient to guide the computerized dendritic arbor. Null model analyses demonstrate that simulated arbors exhibit non-random spatial and topological organization consistent with biological constraints. Our results demonstrate that rules based on a single morphogen gradient are sufficient to generate complex asymmetric dendritic patterns and provide a validated computational framework for testing perturbations in silico. SIGNIFICANCEWe develop and simulate a minimal computational model of dendritic arbor morphogenesis based on a single morphogen gradient. Asymmetric dendrite arbors, such as the ddaE proprioceptive neuron in Drosophila larvae, have not previously been computationally modeled. Using the Dynamical Graph Grammar framework, we create a mathematical model from 17 dynamical rules governing changes in arbor structure, spatial position, morphogen-directed growth, and the local dynamic state of each tip. Each tip switches among three states: growth/pause/shrinkage, while tips that encounter another branch additionally enter a retraction state. Using a large simulation sample size, we characterize our model systems generative outputs and verify that they match imaged biological dendrites across the majority of morphological statistics, including posterior branch bias, branch degree distributions, branch number, and dendrite length. We demonstrate that efficient spacing is guided by the orientation of branch junctions. We make our simulation publicly available to function with high-throughput investigation of gene-to-phenotype relationships in dendrite development.

neuroscience↗

bioRxiv2026

Epidermal and ECM Damage Following Pinch Injury Restricts Dendrite Regeneration in Drosophila

Neuronal dendrites can be injured by a number of insults, but the cellular mechanism by which dendrites respond to tissue injury and undergo repair is poorly understood. Much of the fields progress has evaluated dendrite regeneration following laser injury. While precise, laser injury does not accurately model the real-world damage to surrounding tissue that would accompany neuronal injury. Here, we modify a pinch injury technique to injure both the dendrites and their surrounding tissues in Drosophila melanogaster larvae, more similar to what is observed in real-world injury. We refined this technique such that only half of a sensory neurons dendrites are injured, leaving the other half uninjured. Our data indicate that both dynamic and stable dendritic arbors regrow dendrites following pinch injury. Neurons primarily engage in compensatory regeneration whereby new branches are added on the uninjured half of the arbor. Comparing the regenerative response following pinch versus laser injury revealed that dendrites preferentially regrew into areas where the surrounding tissue was left intact, and not into areas where the surrounding tissue was damaged by pinch. These results prompted us to evaluate the damage sustained to surrounding tissue. In examining non-neuronal tissues after pinch injury, we found damage to epidermal cells and the ECM, but not glia. We also observed a robust immune response on the pinched half of the arbor. We conclude that the sustained damage to surrounding tissue and the initiation of an immune response create a non-permissive environment for dendrite regeneration following pinch injury. Significance StatementNeuronal dendrites are injured in clinical conditions, such as stroke, traumatic brain injury, and neonatal hypoxia. Dendrites also degenerate in the early stages of a number of neurodegenerative diseases. The role of surrounding tissues in dendrite regeneration is poorly characterized, especially considering that neuronal injury is typically accompanied by broad tissue damage. Our data evaluates dendrite regeneration following an injury that better mirrors real-world conditions and demonstrates that broad tissue damage diminishes a neurons capacity to regenerate its dendrites. Our findings show that neurons preferentially regrow into intact, undamaged tissue environments, addressing a large gap in the fields knowledge: how damage to the surrounding tissue limits neuron regeneration after injury. Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=160 SRC="FIGDIR/small/738747v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@1b3f41forg.highwire.dtl.DTLVardef@160284dorg.highwire.dtl.DTLVardef@1f5f6b5org.highwire.dtl.DTLVardef@118208d_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Optimizing CRISPR/Cas9 mutagenesis in Drosophila da neurons to avoid cytotoxicity

Genetic perturbations are one of the great strengths of the model organism Drosophila melanogaster, with approaches such as classical mutagenesis and RNA interference enabling a wealth of biological discoveries. A more recent approach for altering gene expression is CRISPR/Cas9-based mutagenesis, but as with any new tool, its use must be optimized. High expression of Cas9 has been shown to cause cytotoxicity in some cell types. Here, we show that Cas9 expression alone causes cytotoxicity in the dendritic arborization (da) neurons that are widely used to study neuronal development and regeneration. We then systematically evaluate alternative Cas9 transgenes designed to lower total Cas9 expression, called uCas9 transgenes. We show that expression of these uCas9 transgenes results in little to no cytotoxicity to da neurons. Lastly, we demonstrate the ability of uCas9 transgenes to effectively and specifically gene edit in da neuro ns. Thus, we expand the toolkit of genetic perturbations available to researchers working with Drosophila da neurons or other cell types suceptible to cytotoxicity due to high expression of Cas9.

genetics↗

bioRxiv2025

In-vivo dendrite injury drives local mitochondrial contraction and dendrite branching

Mitochondria regulate cellular homeostasis in development and disease, and mitochondrial morphology plays a role in local injury signaling and wound repair. How mitochondria respond during dendrite injury remains an open fundamental question. Here we show that mitochondria contract rapidly and locally after laser dendrotomy. In the proximal intact dendrite, the extent of mitochondrial contraction diminishes with increasing distance from the injury site. We report that mitochondrial contraction is dependent on injury severity and that immediate contraction after injury results in a spatiotemporal increase in dendrite branching. Additionally, we find that mitochondrial contraction is inhibited by KCNJ2 (potassium inwardly rectifying channel subfamily J member 2), providing evidence that mitochondrial contraction is regulated by electrical activity. Mechanistically, we find that injury-induced mitochondrial contraction requires Drp1 (Dynamin related protein 1). In conclusion, these in-vivo findings characterize a dendrite response for mitochondria in neurons and provide insight into the regenerative outcomes of dendrites after injury. Graphical abstractIn-vivo dendrite injury drives local mitochondrial contraction and dendrite branching O_FIG O_LINKSMALLFIG WIDTH=175 HEIGHT=200 SRC="FIGDIR/small/658131v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@e4c767org.highwire.dtl.DTLVardef@1df4f23org.highwire.dtl.DTLVardef@1c4bf4aorg.highwire.dtl.DTLVardef@1ea9f76_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Dendrite injury, but not axon injury, triggers neuroprotection in Drosophila models of neurodegenerative disease.

Dendrite defects and loss are early cellular alterations observed across neurodegenerative diseases that play a role in early disease pathogenesis. Dendrite degeneration can be modeled by expressing pathogenic polyglutamine disease transgenes in Drosophila neurons in vivo. Here, we show that we can protect against dendrite loss in neurons modeling neurodegenerative polyglutamine diseases through injury to a single primary dendrite branch. We find that this neuroprotection is specific to injury-induced activation of dendrite regeneration: neither injury to the axon nor injury just to surrounding tissues induces this response. We show that the mechanism of this regenerative response is stabilization of the actin (but not microtubule) cytoskeleton. We also demonstrate that this regenerative response may extend to other neurodegenerative diseases. Together, we provide evidence that activating dendrite regeneration pathways has the potential to slow-or even reverse-dendrite loss in neurodegenerative disease.

neuroscience↗