The nervous system is comprised of many different cell types, each of which is specialized for a distinct function. Neuronal diversity is generated by the expression of specific signaling genes, as well as via the development of the appropriate morphology and connectivity. The mechanisms by which the acquisition of these multiple aspects of cell fate is coordinated during development to generate a specific neuron type are not well understood. A critical, but poorly understood aspect of sensory neuronal cell fate is the development of specialized sensory cilia which are essential for the fates and functions of sensory neuron types such as photoreceptors and olfactory neurons. Dysfunction of these structures results in retinal degeneration and anosmia. The nematode C. elegans is now well established as a major model organism for the study of ciliogenesis. Cilia are formed via highly conserved mechanisms, and analyses of cilia formation in C. elegans have provided extensive insights into this process in higher animals including humans. A subset of chemosensory neurons in C. elegans exhibits highly diverse and specialized cilia structures. The overall goal of this proposal is to investigate the mechanisms by which specialized sensory cilia are generated and maintained, and to describe the pathways by which the development of these structures is coordinated with other aspects of cell fate to specify a unique neuronal identity.
The Specific Aims are to: 1) Characterize the roles of new genes regulating the specialized cilia morphology of an olfactory neuron type. The molecular identities and roles of two genes will be investigated, and new genes required for the generation of this structure will be identified by a forward genetic screen using novel technologies. 2) Analyze the mechanisms by which sensory activity modulates specialized cilia architecture. Sensory activity plays an important role in maintaining neuron-specific cilia structure. The mechanistic basis for this regulation will be explored, and genes required for this regulation will be identified and analyzed. 3) Analyze the roles of candidate molecules in the formation of the specialized cilia structures. The roles of molecules previously identified via a proteomics-based screen in the formation of neuron-specific cilia structures will be investigated. This reverse genetic approach complements the forward genetic approaches proposed in the first two aims to arrive at a complete description of the pathways leading to the generation of neuron-specific cilia morphology. Ciliary dysfunction has now been implicated in a plethora of diseases collectively called ciliopathies, ranging from anosmia and retinopathies to systemic disorders such as Bardet-Biedl and Joubert syndrome. Given the remarkable conservation of cilia structures across phyla, findings from this work are expected to be directly applicable to higher organisms, and to open up new avenues of investigation.

Public Health Relevance

Primary cilia are present on the majority of cell types in vertebrates, and play critical roles in maintaining cellular homeostasis. Defects in cilia development lead to a range of diseases collectively called ciliopathies which include systemic disorders such as Bardet-Biedl, Joubert, and Meckel-Gruber syndromes among others. Dysfunction of specialized sensory cilia function can result in retinopathies and retinal degeneration, as well as anosmia and hearing loss. Since ciliogenesis mechanisms are highly conserved, the proposed work in C. elegans, a primary model system for the study of cilia development, will provide new information regarding the development of these medically relevant structures.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM056223-17
Application #
8496062
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Sesma, Michael A
Project Start
1997-07-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
17
Fiscal Year
2013
Total Cost
$339,627
Indirect Cost
$124,673
Name
Brandeis University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
616845814
City
Waltham
State
MA
Country
United States
Zip Code
02454
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