The cutaneous somatosensory system processes information that organisms "feel", such as pain, pressure, temperature, and touch. Detection of points, edges, and curvature is mediated by the Merkel cell neurite complex. These complexes consist of slowly adapting type I (SAI) nerve fibers and Merkel cells, and are found at the epidermal-dermal border of glabrous (hairless) skin of the hands and feet, whisker follicles, and specialized regions of hairy skin called touch domes. Cutaneous SAI innervation develops independently of Merkel cell differentiation, and is maintained in the absence of Merkel cells. However, SAI afferents exhibit exuberant terminal branching and loss of prototypical SAI electrophysiological responses in mice that lack Merkel cells. This suggests that Merkel cells may play a role in directing differentiation/maturation of these neurons by currently undefined mechanisms. Despite the critical and fundamental nature of touch, it is the least well understood of all the senses. As such, the molecular pathways that control somatosensory neuron specification and differentiation have been the focus of intense study. A combination of transcription factors and neurotrophin receptors (NTRs) directs the differentiation of somatosensory neurons of the dorsal root ganglia (DRGs). In addition, neurotrophins function in somatosensory neuron survival and neurite outgrowth. The exact mechanisms that govern these processes in SAI afferents, and the explicit sources of the NT signals that direct them, are unknown. This has implications for the treatment of a number of human conditions where there are inherent defects in the somatosensory system (autoimmune diseases, demyelinating diseases, genetic abnormalities, infections, injuries, metabolic disorders, toxic exposures, and vascular disorders).
The aims of this proposal are designed to examine the factors that instruct DRG neurons to assume different aspects of the SAI fiber phenotype. Traditionally, the small number of LTMRs, their random distribution within the highly heterogeneous DRG, and the lack of molecular identity have precluded this type of analysis;however, our laboratory has generated mice lacking Merkel cells, providing us with a unique opportunity to study peripheral control of SAI neuron specification, differentiation, and innervation. The goals of this proposal are: A. To investigate the function of Merkel cells in SAI afferent branching during skin development. Afferent nerves accurately target touch domes that lack Merkel cells, but they display aberrant branching. We will perform a quantitative analysis of SAI afferent branching in K14;Atoh1CKO and wild-type animals to define how branching is altered. This will determine whether the neuron fails to complete its differentiation to a SAI neuron or whether it successfully matures but fails to maintain the fully differentiated state in the absence of Merkel cells. We wil also delete BDNF from Merkel cells and perform quantitative analysis of SAI afferent branching in Atoh1;BdnfCKO and wildtype mice to define whether Merkel cell-derived BDNF plays a role in afferent branching patterns. These experiments will provide a mechanism whereby target innervation instructs neuron morphology. B. To investigate whether Merkel cells are required for DRG neuron subtype differentiation and maintenance. Loss of Merkel cells in the skin results in redistribution of the A? afferent population response. We will examine whether Merkel cells direct differentiation of the SAI or whether they are required for maintenance of the differentiate state. In addition, we will use Merkel dependent-changes in DRG neuron characteristics to identify molecules important in SAI differentiation and maintenance of that fate. These experiments will determine the molecular cascades involved in SAI identity and the peripheral contribution to these processes.
Many different human conditions affect our ability to sense and respond to the world around us. Treatment of these conditions hinges on understanding their pathogenesis, which can only come from understanding the development and maintenance of the somatosensory system. This project addresses the development of the neurons responsible for relaying information regarding curvature, shape, and texture from the skin to the spinal cord. We expect our studies to elucidate general mechanisms controlling sensory neuron development and function and to provide a structure upon which to understand derangements of neuronal development and survival that occur in human disease.
|Reed-Geaghan, Erin G; Wright, Margaret C; See, Lauren A et al. (2016) Merkel Cell-Driven BDNF Signaling Specifies SAI Neuron Molecular and Electrophysiological Phenotypes. J Neurosci 36:4362-76|