A5025004125- Microtubule and mitosis dynamics
- Cellular transport and secretion
- Chromosomal and Genetic Variations
- Ubiquitin and proteasome pathways
- Cellular Mechanics and Interactions
- Wnt/β-catenin signaling in development and cancer
- Developmental Biology and Gene Regulation
- Photosynthetic Processes and Mechanisms
- Hippo pathway signaling and YAP/TAZ
- Genomics and Chromatin Dynamics
- Biotin and Related Studies
- Nerve injury and regeneration
- Silk-based biomaterials and applications
- Genetic and Kidney Cyst Diseases
- Micro and Nano Robotics
- Genetics and Neurodevelopmental Disorders
- 14-3-3 protein interactions
- Supramolecular Self-Assembly in Materials
- Plant Reproductive Biology
- RNA regulation and disease
- CRISPR and Genetic Engineering
- Advanced Materials and Mechanics
- RNA Research and Splicing
- Congenital heart defects research
- Neurobiology and Insect Physiology Research
Pennsylvania State University
2014-2025
Stanford University
2021-2024
Neurons have highly polarized arrangements of microtubules, but it is incompletely understood how microtubule polarity controlled in either axons or dendrites. To explore whether nucleation by γ-tubulin might contribute to polarity, we analyzed neuronal microtubules Drosophila containing gain- loss-of-function alleles γ-tubulin. Both increased and decreased activity γ-tubulin, the core protein, altered dendrites, suggesting a close link between regulation polarity. test locally regulate...
Microtubule minus ends are thought to be stable in cells. Surprisingly, Drosophila and zebrafish neurons, we observed persistent end growth, with runs lasting over 10 min. In Drosophila, extended growth depended on Patronin, Patronin reduction disrupted dendritic minus-end-out polarity. fly dendrites, microtubule nucleation sites localize at dendrite branch points. Therefore, hypothesized might particularly important beyond Distal dendrites have mixed polarity, of lowered the number...
Mutations in >50 genes, including spastin and atlastin, lead to hereditary spastic paraplegia (HSP). We previously demonstrated that reduction of leads a deficit axon regeneration Drosophila model. Axon was similarly impaired neurons when HSP proteins seipin, spichthyin were reduced. Impaired dependent on genetic background observed partial combined with expression dominant-negative microtubule regulators, suggesting work microtubules promote regeneration. Microtubule rearrangements...
Abstract As opposed to syndromic CNVs caused by single genes, extensive phenotypic heterogeneity in variably-expressive complicates disease gene discovery and functional evaluation. Here, we propose a complex interaction model for pathogenicity of the autism-associated 16p11.2 deletion, where CNV genes interact with each other conserved pathways modulate expression phenotype. Using multiple quantitative methods Drosophila RNAi lines, identify range neurodevelopmental phenotypes knockdown...
Dendrite microtubules are polarized with minus-end-out orientation in Drosophila neurons. Nucleation sites concentrate at dendrite branch points, but how they localize is not known. Using Drosophila, we found that canonical Wnt signaling proteins regulate localization of the core nucleation protein γTubulin (γTub). Reduction frizzleds (fz), arrow (low-density lipoprotein receptor-related [LRP] 5/6), dishevelled (dsh), casein kinase Iγ, G proteins, and Axin reduced γTub-green fluorescent...
Microtubule nucleation is important for microtubule organization in dendrites and neuronal injury responses. The core protein, γTubulin (γTub), localized to dendrite branch points Drosophila sensory neurons by Wnt receptors scaffolding proteins on endosomes. However, whether ligands are unknown. We found that secretion from epithelial cells was required γTub localization points. Using RNAi mutant approaches, we demonstrated Wnt4 wntD both position γTub. Moreover, injury-induced increases...
While many regulators of axon regeneration have been identified, very little is known about mechanisms that allow dendrites to regenerate after injury. Using a Drosophila model dendrite regeneration, we performed candidate screen receptor tyrosine kinases (RTKs) and found requirement for RTK-like orphan (Ror). We confirmed Ror was required in two different neuron types using RNA interference (RNAi) mutants. not or normal development, suggesting specific role regeneration. can act as Wnt...
Kinetochores connect centromeric chromatin to spindle microtubules during mitosis. Neurons are postmitotic, so it was surprising identify transcripts of structural kinetochore (KT) proteins and regulatory chromosome passenger complex (CPC) assembly checkpoint (SAC) in Drosophila neurons after dendrite injury. To test whether these function regeneration, postmitotic RNA interference (RNAi) performed dendrites or axons were removed using laser microsurgery. Reduction KT, CPC, SAC decreased...
Axon injury can lead to several cell survival responses including increased stability and axon regeneration. Using an accessible Drosophila model system, we investigated the regulation of their relationship. stabilizes rest cell, entire dendrite arbor. After found mitochondrial fission in dendrites was upregulated, that reducing stabilization or neuroprotection (NP). Thus seems both turn on NP, but also dampen it by activating fission. We identified caspases as negative regulators...
In Drosophila neurons, kinesin‐2, EB1 and Apc are required to maintain minus‐end‐out dendrite microtubule polarity, we previously proposed they steer microtubules at branch points. Motor‐mediated steering of plus ends could be accomplished in two ways: 1) by linking a growing tip the side an adjacent as it navigates point (bundling), or 2) directing after collision with stable (collision resolution). Using live imaging distinguish between these mechanisms, found that reduction kinesin‐2 did...
We previously identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental outcomes, where severely affected probands carried an excess of rare pathogenic variants compared to mildly carrier parents. hypothesized the sensitizes genome for disease, while “second-hits” in genetic background modulate phenotypic trajectory. To test this model, we examined how defects conferred by knockdown individual homologs are modulated simultaneous...
In Drosophila neurons, uniform minus-end-out polarity in dendrites is maintained part by kinesin-2-mediated steering of growing microtubules at branch points. Apc links the kinesin motor to microtubule plus ends and Apc2 recruits points where it functions. Because acts concentrate other proteins points, we wished understand how targeted. From an initial broad candidate RNAi screen, found Miro (a mitochondrial transport protein), Ank2, Axin, spastin Rac1 were required position Apc2-GFP...
Axons and dendrites are distinguished by microtubule polarity. In Drosophila, dominated minus-end-out microtubules, whereas axons contain plus-end-out microtubules. Local nucleation in generates microtubules both orientations. To understand why dendritic does not disrupt polarity, we used live imaging to analyze the fate of generated at branch points. We found that they had different rates success exiting based on orientation: correctly oriented succeeded leaving about twice as often...
Planar cell polarity (PCP) signaling polarizes cells within the plane of an epithelium. In airways, planar orients directional beating motile cilia required for effective mucociliary clearance. The mechanism is best understood from work in Drosophila, where it has been shown to both coordinate axis between and direct morphological manifestations polarization cells. 'core' comprises two protein complexes that segregate opposite sides each interact with complex neighboring Proper subcellular...
Abstract Planar Cell Polarity (PCP) signaling polarizes epithelial cells in a plane orthogonal to their apical-basal axis. A core PCP module both generates molecular asymmetry within and coordinates the direction of polarization between neighboring cells. Two subcomplexes proteins segregate opposite sides cell, defining polarity Homodimers atypical cadherin Flamingo are thought be scaffold upon which these assemble required for intercellular signaling. The central role homodimers scaffolding...
The planar cell polarity (PCP) signaling pathway polarizes epithelial cells in the tissue plane by segregating distinct molecular subcomplexes to opposite sides of each cell, where they interact across intercellular junctions form asymmetric clusters. role clustering this process is unknown. We hypothesized that protein cluster size distributions could be used infer underlying dynamics and function assembly polarization. developed a method count number monomers core PCP proteins within...
ABSTRACT As opposed to syndromic CNVs caused by single genes, extensive phenotypic heterogeneity in variably-expressive complicates disease gene discovery and functional evaluation. Here, we propose a complex interaction model for pathogenicity of the autism-associated 16p11.2 deletion, where CNV genes interact with each other conserved pathways modulate expression phenotype. Using multiple quantitative methods Drosophila RNAi lines, identified range neurodevelopmental phenotypes knockdown...
Abstract We previously identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental outcomes, where severely affected probands carried an excess of rare pathogenic variants compared to mildly carrier parents. hypothesized the sensitizes genome for disease, while “second-hits” in genetic background modulate phenotypic trajectory. To test this model, we examined how defects conferred by knockdown individual homologs are modulated...
PCP signaling polarizes epithelial cells within the plane of an epithelium. Core components adopt asymmetric subcellular localizations to both polarize and coordinate polarity between cells. Achieving asymmetry requires additional effectors, including some mediating post-translational modifications core components. Identification such proteins is challenging due pleiotropy. We used mass spectrometry-based proximity labeling proteomics identify regulators in Drosophila wing. identified...