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Overview
Overview
Cilia are ubiquitous, microtubule-based organelles that protrude from the cell surface and perform diverse biological functions, including fluid movement, mechanosensation, and cell signaling. Defects in ciliary structure or function are associated with a broad spectrum of disorders, collectively known as ciliopathies, including polycystic kidney disease, retinal degeneration, intellectual disability, chronic airway disease, hydrocephalus, metabolic disorders, and infertility.
Our laboratory investigates how cilia and ciliary proteins regulate mammalian development, tissue function, and disease pathogenesis. We combine mouse genetics, cultured cell models, advanced imaging, biochemistry, and structural approaches to define the molecular mechanisms that control ciliogenesis and cilia-mediated signaling. Our projects provide opportunities for students and trainees interested in cell biology, developmental biology, neuroscience, genetics, imaging, and disease mechanisms.
Roles of ciliary proteins in mammalian development and disease
We have generated a series of unique mouse models lacking specific ciliary genes, many of which develop striking phenotypes that recapitulate features of human ciliopathies. These models provide powerful opportunities to investigate how defects in ciliary structure and function lead to developmental abnormalities, tissue dysfunction, and disease.
Control and CEP164-KO P18 mice, showing hydrocephalus in the KO (left), and IF staining of the adult subventricular zone for cilia (green) and cell boundaries (red), showing reduced cilia in the KO (right). Scale bar, 25 μm. See Siller et al. 2017.
Exocrine pancreatic degeneration in Cby1-KO mice. Cby1-KO pancreatic tissue is outlined by the dotted line. The arrow indicates ectopic adipose tissue in the Cby1-KO pancreas. See Cyge et al. 2021.
Left–right asymmetry defects in ciBAR1-KO mouse embryos. E9.5 embryos showing opposite tail curvature in ciBAR1-KO compared with WT, consistent with defective nodal cilia function. See Kim et al. 2024.
Super-resolution and ultrastructural imaging of ciliary structures and protein localization
A major strength of our laboratory is the use of advanced imaging approaches to study the organization, localization, and dynamics of ciliary proteins. We use a broad range of imaging modalities, including confocal microscopy, SIM, STORM, TEM, SEM, and cryo-ET. These approaches allow us to define the nanoscale organization of ciliary proteins and examine the architecture of cellular organelles and macromolecular assemblies at high resolution. We also use live-cell imaging to investigate ciliary protein dynamics and vesicle trafficking during ciliogenesis.
3D-STORM image of the Cby1 ring substructure in cultured tracheal ciliated cells, shown in a top-down view. See Burke et al. 2014.
ExM-SIM image showing a lateral view of Cby3 (green) and SEPT4 (white) rings at the annulus in a differentiating mouse spermatozoon. Scale bar, 272 nm. See Hoque et al. 2024.
Spinning disk confocal time-lapse of EGFP-Centrin1 in CEP164-KO mouse round spermatids. White arrowheads mark the initial positions of centriole pairs. Defective basal body docking leads to centriole migration through intercellular bridges and formation of large aggregates. Large round green structures are autofluorescent floating cells. See Chen et al. 2026.
Vesicle trafficking and membrane remodeling in cell signaling and organelle biogenesis
Ciliogenesis requires the coordinated trafficking of membrane lipids and cargo proteins from the Golgi and endosomal compartments to the developing cilium. However, the molecular mechanisms that drive membrane delivery, remodeling, and basal body-membrane interactions remain incompletely understood. Our laboratory has shown that the ciliary protein Cby1 interacts with lipid-binding ciBAR proteins and promotes their association with membranes. We are now investigating how these membrane-binding and remodeling activities contribute to ciliogenesis using complementary approaches, including in vitro reconstitution with purified proteins and lipids, cell-based functional studies, and structural analysis by cryo-ET.
Immuno-EM localization of Cby1 in early ciliated cell differentiation in MTEC cultures. Cby1 protein (arrowheads) localizes to the distal appendages of migrating basal bodies in the cytoplasm, where small vesicles are tethered. See Burke et al. 2014.
Model illustrating the proposed role of the Cby1/ciBAR1 complex in cilium budding through membrane binding and curvature regulation. The Cby1/ciBAR1 complex is recruited by CEP164 to the distal end of the basal body, where it binds to phosphoinositide-enriched membranes and may induce or maintain local membrane curvature, facilitating ciliary membrane protrusion and cilium budding. CV, ciliary vesicle; DA, distal appendage; SDA subdistal appendage; BB basal body. Credit: Eunice Kim.
Overall, our research seeks to uncover fundamental mechanisms of cilia assembly and signaling and to understand how disruption of these processes contributes to human disease. Trainees in the laboratory have opportunities to work at the interface of basic cell biology, developmental genetics, advanced imaging, and clinically relevant disease models.
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