The molecular basis of the development and diversity of proprioceptive neurons : a story of surviving and thriving

Proprioception, also known as the sixth sense, describes the sensation of our body position and movement. Its proper function is essential for our daily activities from coarse movements, e.g. locomotion, to precise movements, e.g. playing instruments. The key executors of proprioception are proprioceptive neurons (PNs), the peripheral sensory neurons which continuously monitor the status of muscles, and provide feedback to the central circuits to regulate motor outputs. This thesis aims to extend our current understanding of the development (study I) and functional organization (study II) of PNs. To contextualize the two studies, this thesis first reviews the relevant literatures in the chapter of Introduction, followed by the presentation of the major findings.

In study I, we revisit the long-standing neurotrophic hypothesis, which features the exclusive role of target-derived factors in controlling programmed cell death in developing nervous system. Using PNs as a model, we try to understand whether neurons themselves are actively engaged or passively selected during this competition to survive. We find that right before the cell death period, PNs exhibit diverse molecular profiles, which underlie their different responsiveness to target-derived factors and maturation states. The PNs with certain molecular signatures out compete others in this selection to survive, showing that the intrinsic properties of neurons endow some neurons with competitive advantages and are involved in the regulation of neuronal death together with environmental factors.

In study II, we use single-cell RNA sequencing to analyze the molecular profiles of adult PNs in mice. Through immunological, genetic and viral labeling, we identify three groups of PNs that correspond to the known functional subtypes (Ia, Ib and II) and provide long-awaited genetic markers to target them individually. We also unveil subtypes within Ia- and II-PNs (Ia1/2/3-PNs and II1/2/3/4-PNs) that have stereotyped distribution along the spinal cord, selective muscle targets, and unique molecular attributes, indicating an unanticipated and sophisticated organization of proprioceptive feedback. While all other subtypes are established neonatally before the onset of coordinated movements, Ia-PN subtypes emerge later along with the maturation of the animal’s motor skills, suggesting the influence of sensory experience on the diversification of Ia-PN subtypes. This is supported by the experiment in which Ia-PN subtypes adjust their relative abundance (Ia1-PNs switch to Ia2/3-PNs) after sustained exercise training, showing the plasticity of the proprioceptive system to adapt to changing motor activity.

List of scientific papers

I. Wang Y*, Wu H*, Fontanet P, Codeluppi S, Akkuratova N, Petitpré C, Xue-Franzén Y, Niederreither K, Sharma A, Da Silva F, Comai G, Agirman G, Palumberi D, Linnarsson S, Adameyko I, Moqrich A, Schedl A, La Manno G, Hadjab S, Lallemend F. A cell fitness selection model for neuronal survival during development. Nature Communications. 2019 Sep 12;10(1):4137. *Co-first authors.
https://doi.org/10.1038/s41467-019-12119-3

II. Wu H, Petitpré C, Fontanet P, Sharma A, Bellardita C, Quadros RM, Jannig PR, Wang Y, Heimel JA, Cheung KKY, Wanderoy S, Xuan Y, Meletis K, Ruas J, Gurumurthy CB, Kiehn O, Hadjab S, Lallemend F. Distinct subtypes of proprioceptive dorsal root ganglion neurons regulate adaptive proprioception in mice. Nature Communications. 2021 Feb 15;12(1):1026.
https://doi.org/10.1038/s41467-021-21173-9