Gene-expression studies of epidermal Merkel cells

University Of California San Francisco, San Francisco CA

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Abstract

DESCRIPTION (provided by applicant): The long-term goal of this research is to elucidate the molecular basis of mechanotransduction by mammalian somatosensory receptor cells using the cutaneous Merkel cell-neurite complex as a model. Somatosensory mechanoreceptors mediate the senses of touch, pain and proprioception. The importance of these senses to human health is underscored by diseases that cause peripheral neuropathy such as rheumatoid arthritis, diabetes and acquired immunodeficiency syndrome. Because patients with peripheral neuropathy cannot feel injuries, even minor insults can lead to irreversible tissue damage and chronic pain. Although Merkel cells are conserved throughout vertebrate evolution, their function is unknown. Merkel cells have been proposed to be mechanoreceptors that transduce pressure and convey this information to the nervous system through synaptic transmission. Alternatively, Merkel cells may influence the activity of mechanosensory neurons through the release of neuromodulators. Finally, Merkel cells may affect the development of touch responsiveness, either by influencing the innervation patterns of sensory neurons or by directing neighboring epidermal cells to form specialized skin structures that are highly sensitive to touch. The objective of this application is to distinguish between these proposed functions by developing molecular and in vitro tools. First, we will use mouse DNA microarrays to identify gene-expression profiles of Merkel cells during and after maturation of the sense of cutaneous touch. Second, we will develop methods for studying ion channels and neurotransmitter release in dissociated Merkel cells. These in vitro methods will then be used to examine the roles of Merkel-cell-enriched molecules in signaling. By pinpointing molecules that may be essential for Merkel-cell signaling, these studies lay the groundwork for future investigation of the role of this epidermal cell in touch reception, and of the signals that initiate our perception of touch and pain. The proposed Specific Aims are: 1. Identify transcripts that are enriched in Merkel cells 2. Define the ionic conductances of dissociated Merkel cells 3. Characterize neurotransmitter release from Merkel cells in vitro