Cilia are microtubule-based cellular protrusions with diverse biological functions, including fluid movement, cellular locomotion, environmental sensing, and signal transduction. Traditionally, most cilia are classified based on differences in ciliary ultrastructure, biological function, and ciliary motility, with primary cilia and motile cilia as the major categories. The primary cilia functions as solitary sensory hubs to transduce extracellular stimuli into intracellular signaling pathways, and the motile cilia exhibited coordinated beating to generate directional fluid movement. Choroid plexus epithelial cells contain multi-sensory cilia that regulate the production of cerebrospinal fluid (CSF) to support neuronal development and physiology. Using serial transmission electron microscopy (TEM) and focus ion beam scanning electron microcopy (FIB-SEM), our preliminary results suggest that the multi-sensory cilia of choroid plexus represent a distinct type of cilia, exhibiting unique ultrastructural features, while resembling aspects of both primary cilia and motile cilia. Defective ciliogenesis in choroid plexus causes hydrocephalus, at least in part, due to CSF overproduction. Choroid plexus cilia are likely to play an important role in Shh signaling, as FoxJ1 deficient choroid plexus cilia no longer respond to Shh treatment in explant culture. We discovered a functional connection between Shh signaling and Aqp1 expression. Hence, we hypothesize that choroid plexus cilia are a unique type of multi-sensory that mediate Shh signaling to regulate CSF production, at least in part, by regulating the expression of water channels and ion transporters. Here, using a combined approach of advanced imaging techniques, mouse genetics, imaging studies, cell biology and molecular biology, we propose to study the ciliary ultrastructures, ciliogenesis mechanisms and biological functions of the multi-sensory cilia of choroid plexus. First, using electron microscopy, FIB-SEM and super-resolution imaging, we will characterized the ultrastructure of choroid plexus cilia, and define their developmental dynamics at different developmental stages. Second, we will employ mouse genetics and genomics studies to identify and characterize the ciliogenesis machineries of choroid plexus cilia. Finally, we will elucidate the molecular mechanisms through which dynamic choroid plexus cilia mediate the Shh signaling to regulate CSF production. Taken together, the proposed studies will structurally and functionally define a new type of multi-sensory cilia in choroid plexus, and will generate important insights on the molecular basis for the regulation of CSF production.

Public Health Relevance

Choroid plexus cilia are a new type of multi-sensory cilia structurally distinct from primary or motile cilia. These cilia play an important role in regulating the production of cerebrospinal fluid during development and physiology. Using advanced imaging techniques, mouse genetics and genomics, cell and molecular biology approaches, our proposed studies aim to characterize the ultrastructure of choroid plexus cilia, characterized their developmental dynamics, and elucidate the molecular basis for their regulation on cerebrospinal fluid production.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Morris, Jill A
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University of California Berkeley
Schools of Arts and Sciences
United States
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