Molecular mechanisms of
sensory cilia formation and function
Primary immotile cilia are microtubule-based organelles that have been referred to as cellular antennae. Although primary cilia were long thought to be present only on a subset of cells, it is now clear that nearly all cells in metazoans are ciliated. Primary cilia house signaling molecules, and play critical roles in maintaining cellular functions in a broad range of cell types, including neurons in the mammalian peripheral and central nervous systems. The importance of cilia in regulating cellular homeostasis is highlighted by the finding that ciliary dysfunction underlies a plethora of disorders, now collectively termed ciliopathies.
The overall goals of this subproject are to explore the mechanisms by which cilia form and function, and to define how altered ciliary signaling contributes to changes in cellular and organismal behavior and homeostasis.
Methods used: genetics, molecular biology, live imaging, confocal microscopy, in vivo calcium imaging
3D reconstruction model of all sensory cilia and associated glial cells in the amphid sensory organs in the C. elegans nose (from serial section transmission electron micrographs). From Doroquez, Berciu et al, 2014 eLife
C. elegans
C. elegans is an established model organism for studying cilia formation and function. Unlike in mammals, only a subset of sensory neurons in C. elegans is ciliated, allowing us to study cilia function in defined cell types in vivo. Sensory cilia house sensory signaling molecules and are absolutely essential for sensory signal transduction. Molecular mechanisms for ciliogenesis and cilia function are remarkably conserved from the blue-green alga Chlamydomonas to humans, allowing us to exploit the experimental power of C. elegans to understand how these important organelles form, and how they contribute to, and regulate, cellular functions. We have identified several new and conserved molecules required for sensory ciliogenesis, described new mechanisms of ciliary signaling protein trafficking, and used serial section electron microscopy and tomography to describe the 3D structures of individual sensory cilia at high resolution (in collaboration with Daniela Nicastro).
Some of the questions that interest us:
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How are the unique morphologies of individual sensory cilia generated and maintained?
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How do these distinct cilia morphologies shape the sensory functions of the neurons?
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What are the mechanisms by which signaling proteins are localized to specific cilia subdomains?
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How does neuronal activity modulate cilia structure?
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How does cilia organization within a sense organ and cilia-cilia contact influence neuronal properties?
Rodents
We have also recently initiated a collaboration with Gina Turrigiano to explore the roles of cilia in the mature vertebrate brain. While cilia are known to play important roles in neuronal development and migration in the immature brain, their roles in the adult brain are not well understood. Our recent work suggests that ciliary signaling may modulate synaptic strength in the postnatal rodent brain.
Some of the questions that interest us:
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Does ciliary signaling modulate both excitatory and inhibitory synaptic number and strength?
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What are the modulators and cognate receptors that act via the cilia to alter synaptic properties?
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How are signals from cilia translated into changes in synaptic functions?
Rat cortical neurons stained with anti-NeuN (magenta) and anti-Arl13b antibodies to indicate cilium (green). Image taken by Lauren Tereshko.
NIH R21 MH118464