Sensory modalities such as pain, touch, and proprioception serve a crucial role in conveying information regarding the external and internal environment. Recent years have seen progress in defining the molecular basis of nociceptor and touch receptor subtypes, but proprioceptor subtype diversity remains poorly understood at both a cellular and molecular level. Proprioceptive muscle feedback is critical in the planning and adjustment of motor output and derives from three main proprioceptor subclasses: group Ia and group II muscle spindle (MS) afferents, and group Ib Golgi tendon organ (GTO) afferents. But, without genetic access to the individual proprioceptor subtypes, their specific contributions to the execution of coordinated motor movement remain unknown. Proprioceptive sensory neurons (pSNs) extend axons to their peripheral muscle receptors shortly after they establish a `generic' pSN identity. The prevailing view is that proprioceptor MS/GTO subclass identity is determined at these early embryonic stages through intrinsic genetic programs. However, our recent studies identified several transcripts that are preferentially expressed in subsets of proprioceptors after they innervate their MS and GTO sensory organs. Moreover, for at least one of these transcripts expression appears to depend on the presence of sensory receptors. Thus, while it is possible that these transcripts merely reflect differences in MS/GTO afferent maturation, our findings have begun to question the notion that proprioceptor MS/GTO subtype identity strictly depends on intrinsic transcriptional programs. Instead, we hypothesize that i) proprioceptor subclass identity is acquired though a protracted process with a gradual induction and/or selective maintenance of subclass specific transcripts, and ii) is in part induced by retrograde signals from their peripheral sensory organs. This proposal test these ideas through three sets of experiments. First, we will combine viral and genetic strategies to assign a MS (group Ia/II) or GTO (group Ib) subclass identity to a selected set of candidate proprioceptor subtype markers, and test the requirement of these molecules in proprioceptor subtype acquisition. Second, we will take advantage of single cell transcriptome sequencing technologies to delineate the molecular dynamics through which pSN MS/GTO subclass identities emerge during development. Third, we will assess the role of extrinsic signaling molecules in directing pSN subclass identity. Together these studies will provide a comprehensive understanding of the molecular basis of proprioceptor subclass identity, thus permitting renewed efforts to delineate the role of these important sensory neurons in motor control at both a physiological and circuit level.
The proposed studies will result in a molecular understanding of proprioceptor subtype identity and of the developmental mechanism through which these important sensory subtypes emerge. The identification of molecules that distinguish between pSN subclasses permits genetic strategies to dissect the contribution of MS and GTO afferents in the execution of coordinated motor behavior. Insight into the physiological roles of the distinct pSN subclasses in motor control will have profound implications for the development of new neuroprosthetic devices that incorporate muscle sensory feedback. At a separate level, a better understanding of the signaling factors that promote proprioceptor development/specification will inform efforts to derive these neurons from induced pluripotent stem cells (iPSCs) and will enable new models of peripheral neuropathy to develop better preventive or therapeutic strategies to combat these disorders.
