Neuron-Schwann cell interactions are important for the development, function, and regeneration of the peripheral nervous system (PNS). Perturbations in this crosstalk can cause debilitating diseases, such as Charcot- Marie-Tooth disease and other peripheral neuropathies. However, the molecular nature of the interactions between axons and different classes of Schwann cells and the regulation of these interactions are not fully understood. In this proposal, I will determine how the transcription factor Er81 controls development of Pacinian corpuscles, which are specialized sensory end organs composed of a single myelinated sensory axon and non-myelinating corpuscle-forming Schwann cells. Er81 mutant mice have no Pacinian corpuscles, and my preliminary data suggest that the primary deficit comes from disrupted axon-Schwann cell interactions. Since Er81 is a transcription factor, this effect must be executed by other downstream effectors. Neuregulin-1 (Nrg1) is a key mediator of axon-Schwann cell interactions. The expression level of an isoform of Nrg1 with cysteine rich extracellular domain (Nrg1-CRD) determines the thickness of myelination of peripheral axons. In addition, the development of muscle spindles, which contain sensory axons, muscle fibers, and non-myelinating Schwann cells, requires other Nrg1 isoforms, most likely those with an Ig-like extracellular domain (Nrg1-Ig). Despite the important functions of Nrg1, how Nrg1 is regulated to acquire an appropriate expression level is completely unknown. Interestingly, I found that Er81 mutant mice display decreased expression of both isoforms of Nrg1 in somatosensory neurons and reduced myelination thickness of peripheral axons. Therefore, I hypothesize that Er81 regulates the expression of multiple isoforms of Nrg1 to control axonal interactions with both myelinating and non-myelinating Schwann cells.
In Aim 1, I will determine that Er81 is required in neurons to maintain a high level of myelination of large-diameter somatosensory axons. I will quantify the extent of the downregulation of Nrg1-CRD and Nrg1-Ig in Er81 mutant somatosensory neurons, and demonstrate that Er81 regulates Nrg1 expression by direct binding to the Nrg1 promoter. To place Nrg1 downstream of Er81 in Pacinian corpuscle development, I will rescue Pacinian corpuscles in Er81 mutant mice by ectopically supplying Nrg1.
In Aim 2, I will determine the role of Nrg1 in Pacinian corpuscle formation by ablating all isoforms of Nrg1 from somatosensory neurons. I will also determine which isoforms of Nrg1 are required for corpuscle formation through rescue experiments and analyzing isoform specific mutant mice. Lastly, I will examine if a high level of Nrg1 is sufficient to induce the formation of Pacinian corpuscles in an ectopic location, the mouse foot pad. Collectively, anticipated results from my work will identify the firs transcriptional mechanism that controls the extent of myelination of PNS axons via the regulation of Nrg1, and elucidate molecular mechanisms of neuronal interaction with non-myelinating Schwann cells.
Interactions between neurons and Schwann cells are critical for the development, function, and regeneration of the peripheral nervous system. In this proposal, I aim to understand a key transcriptional mechanism which controls interactions between sensory neurons and different types of Schwann cells. Results from this work will improve our understanding of the normal development of the peripheral nervous system and could have implications for potential treatment of diseases of the peripheral nervous system.
|Cui, Lian; Miao, Xuerong; Liang, Lingli et al. (2016) Identification of Early RET+ Deep Dorsal Spinal Cord Interneurons in Gating Pain. Neuron 91:1137-53|
|Fleming, Michael S; Li, Jian J; Ramos, Daniel et al. (2016) A RET-ER81-NRG1 Signaling Pathway Drives the Development of Pacinian Corpuscles. J Neurosci 36:10337-10355|
|Olson, William; Dong, Peter; Fleming, Michael et al. (2016) The specification and wiring of mammalian cutaneous low-threshold mechanoreceptors. Wiley Interdiscip Rev Dev Biol 5:389-404|