Current Research Projects
Rab11.1-Positive Vesicle (Purple) Trafficking Along Microtubules (Green).
What Determines Motor Biology and Structure in Neurons?
Our lab studies the interplay between microtubule stability, dynamics, and various cellular components to enhance our understanding of neuronal development and function. Studying fundamental neuronal microtubule and motor biology in vivo is essential for understanding how neurons maintain their structure and function, as microtubules are critical for cellular transport and signaling. Our research focuses on microtubule stability and dynamics to maintain a functional microtubule array, identifying proteins that promote stability or facilitate dynamics during neurite outgrowth, as well as investigating the role of RAB GTPases in regulating transport along microtubules. Additionally, we are exploring how lysosomal biology, and the endoplasmic reticulum-plasma membrane gap junctions, play an integral part in neuronal function.
GFP-Labeled PVD Neuron in C. elegans.
What Interactions Underly Dendrite Morphogenesis?
A foundational concept in biology is the regulation of pathways through Receptor-Ligand interactions. In developing neurons, some pathways influence dendrite growth and synapse formation, and disruptions here lead to neurodevelopmental disorders and diseases. Our lab identified that the ligands SAX-7, MNR-1, and LECT-2 interact with the receptor DMA-1 to influence the formation of the dendrites in PVD, a neuron in C. elegans, where unbound DMA-1 promotes dendrite growth. Building off this work, we are actively looking to determine upstream and downstream pathways that affect this process, as well as characteristics of each protein separately to understand the mechanisms. We are also researching axonal guidance features and how dendrites determine an efficient receptive field.
GFP-Labeled PVD Neuron in C. elegans at L4 stage.
What Interactions Underly Dendrite Morphogenesis?
A foundational concept in biology is the regulation of pathways through Receptor-Ligand interactions. In developing neurons, some pathways influence dendrite growth and synapse formation, and disruptions here lead to neurodevelopmental disorders and diseases. Our lab identified that the ligands SAX-7, MNR-1, and LECT-2 interact with the receptor DMA-1 to influence the formation of the dendrites in PVD, a neuron in C. elegans, where unbound DMA-1 promotes dendrite growth. Building off this work, we are actively looking to determine upstream and downstream pathways that affect this process, as well as characteristics of each protein separately to understand the mechanisms. We are also researching axonal guidance features and how dendrites determine an efficient receptive field.
Human iPSC-derived cortical neurons stained for Map2 and Tuj1.
What are the Mechanisms of Neuronal Stress Resilience?
Neuronal stress, as a result of conditions like oxidative stress, excessive stimulation, or other dysfunction, can impair cellular function or lead to cell death. Understanding neuronal stress is crucial because it plays a key role in development, where abnormalities and inefficiencies can cause neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. Our lab is investigating mechanisms that protect against stress in C. elegans, particularly in endosomal stress and the integrated stress response. For greater context, our lab is also examining these pathways in human iPSC-derived neurons to demonstrate similarities in pathways and function.
Recent Findings from our Lab
Below are some summaries of other projects that were done in the lab.
Active zone formation through phase separation is regulated by kinase activity
Active zones in the presynapse are critical structures for the function of neurons, setting the stage for synaptic vesicle cargo release into the synaptic cleft for signal transduction. The active zone is comprised of several scaffolding proteins. One of these proteins in Caenorhabditis elegans is SYD-2, which we showed previously to undergo phase separation along with ELKS-1, another scaffolding protein, to assemble the active zone in the HSN neuron. Recently, we found that the kinase SAD-1 activates SYD-2/Liprin-α through phosphorylation. Phosphorylated SYD-2/Liprin-α lacks binding interactions between two domains in its folded structure, which inhibits phase separation and promotes autoinhibition in wildtype conditions. With these intrinsic binding interactions absent, the scaffold protein is allowed to phase separate for the construction of the active zone.
Ligand-free and ligand-bound DMA-1 Influence dendritic arbor in receptor-ligand interactions.
The formation of dendritic branches in neurons involves dynamic and random growth, but it’s unclear how receptors and ligands control this process. We found that the guidance receptor DMA-1 and its ligand SAX-7/LICAM influence the shape of the PVD sensory neuron in C. elegans. We discovered that the binding of the ligand to DMA-1 doesn’t promote dendritic growth but instead inhibits it, preventing branch retraction, and altering the arbor from its usual menorah-like shape. Dendritic growth relies on a pool of ligand-free DMA-1, which is maintained through receptor recycling. Mutants with defective DMA-1 recycling show abnormal dendrite development. We propose ligand-free DMA-1 drives random growth, while ligand binding refines the final dendritic structure by limiting growth.
One factor that determines neuronal fate is the repression of non-neuronal genes
Cellular differentiation requires the activation of target cell transcriptional programs and suppression of non-target cell programs. The Myt1 family of zinc finger transcription (ztf) factors aids fibroblast to neuron reprogramming in vitro. In C. elegans, the Myt1 homolog ztf-11 is essential for neurogenesis in several neuronal lineages, including cells undergoing epithelial-to-neuronal transdifferentiation.
The gene ztf-11 is specifically expressed in neuronal precursors at the single-cell level. When ztf-11 is lost, non-neuronal genes are upregulated, leading to reduced neurogenesis. Conversely, ectopic ztf-11 expression in epidermal cells can generate additional neurons. ZTF-11 works with the MuvB corepressor complex to repress non-neuronal gene activation in neurons. Our finding aligns with Myt1l’s role in driving neuronal transdifferentiation in vertebrates, revealing a conserved mechanism for defining neuronal fate by repressing non-neuronal genes.