Multiple Roles of Ret Signaling in Mechanosensory Neuron Development

Somatosensation is critical for interaction with the surrounding environment. Somatosensory stimuli are detected by primary somatosensory neurons of the dorsal root ganglia and trigeminal ganglia, which detect distinct classes of stimuli, such as temperature, pain, and pressure. In Chapters 2 and 3 of this thesis, we focus on rapidly adapting low-threshold mechanoreceptors (RALTMRs), which mediate the detection of light touch. RALTMRs are molecularly defined by the early embryonic expression of the receptor tyrosine kinase Ret. Ret is required for the development of central axonal projections of RALTMRs into the dorsal spinal cord. RET responds to the glial cell line-derived family of neurotrophic factors, which activate RET in combination with GPI-linked GFRα co-receptors. In vitro, RET can be activated by co-receptor expressed in the same cell (cis signaling) or by co-receptor expressed by neighboring cells (trans signaling), but previous studies suggest that trans RET signaling may not play a physiologically relevant role in vivo. Here, we show that RET in mouse RALTMRs can be activated by both GFRα2 expressed in the same cell (cis signaling) and GFRα1 expressed by neighboring cells (trans signaling), and that trans RET signaling is sufficient for the development of RALTMR central projections in vivo. Peripherally, Ret is required for the development of vibration sensitive Pacinian corpuscle RALTMR end organs. We show that Ret mediates the neuronal expression of the ETS transcription factor Er81, which is also required for Pacinian corpuscle development, and that deficient axon/Schwann cell communication is the primary deficit in Pacinian corpuscle development in Er81 mutant mice. Furthermore, we show that Neuregulin-1, an important mediator of axon/Schwann cell interactions, is required for Pacinian corpuscle development, and that Er81 regulates the expression of specific Neuregulin-1 isoforms. In total, we demonstrate that RET signaling drives the development of distinct developmental processes in both the central and peripheral axonal branches of RALTMRs. In Chapter 4, we describe the expression of itch-related neuropeptides GRP and NMB and their receptors in somatosensory neurons and the dorsal spinal cord.