The long-term goal of the proposed research is to understand how cells monitor and respond to changes in the structure of their interacting cells. Cell structure is critical for cell function and the cells in the nervous system, neurons and glia, have particularly elaborate structures. Structural defects in both neurons and glia are associated with disease and experience-dependent structural remodeling of neuronal receptive endings (NREs) is proposed to correlate with learning and memory. Cells monitor and respond to the structure of their interacting cells; indeed, there are several well-studied examples of glial monitoring of neuronal structure. Despite this, relatively little is known about how glia respond to physiological changes or pathological defects in NRE structure. One clear example of glia monitoring NRE structure occurs in the C. elegans amphid sensory organ; animals with defective NRE cilia exhibit a response in their ensheathing glia including accumulation of secretory vesicles and changes in protein expression and localization. This proposal seeks to elucidate the molecular basis of glial structural monitoring of NREs and the glial response to NRE structural defects in the C. elegans amphid sensory organ. To rigorously investigate these mechanisms, this F32 proposal combines critical training in computational skills with cell biology and genetics approaches to the following specific aims: (1) define the cellular basis of glial monitoring of NRE structure; (2) characterize the cell biological and transcriptional glial response to NRE structural defects; and (3) identify molecules involved in glial monitoring of NRE structure. These studies have the potential not only to elucidate the general principles of glial structural monitoring of NREs, but may also reveal glial responses that occur in ciliopathies, human disorders defined by genetic mutations affecting cilia formation. The mechanisms and molecules uncovered here may also be at work in glial sensing of physiological structural changes that occur in NREs during development and upon experience.
The structure of neuronal receptive endings is critical for their function; indeed, experience-dependent structural remodeling of neuronal receptive endings is associated with learning and memory and structural defects are associated with disease. Glia are critical regulators of neuronal structure and monitor the structure of neurons in several settings, yet how glia monitor and respond to changes in neuronal receptive ending structure remains unclear. This study will elucidate how glia monitor and respond to structural changes in neuronal receptive endings at the cellular and molecular level in the C. elegans amphid sensory organ, in which glial responses to structural defects in neuronal receptive endings have been defined.
