ERR2 and ERR3 promote the development of gamma motor neuron functional properties required for proprioceptive movement control

PLoS Biol. 2022 Dec 21;20(12):e3001923. doi: 10.1371/journal.pbio.3001923. eCollection 2022 Dec.


The ability of terrestrial vertebrates to effectively move on land is integrally linked to the diversification of motor neurons into types that generate muscle force (alpha motor neurons) and types that modulate muscle proprioception, a task that in mammals is chiefly mediated by gamma motor neurons. The diversification of motor neurons into alpha and gamma types and their respective contributions to movement control have been firmly established in the past 7 decades, while recent studies identified gene expression signatures linked to both motor neuron types. However, the mechanisms that promote the specification of gamma motor neurons and/or their unique properties remained unaddressed. Here, we found that upon selective loss of the orphan nuclear receptors ERR2 and ERR3 (also known as ERRβ, ERRγ or NR3B2, NR3B3, respectively) in motor neurons in mice, morphologically distinguishable gamma motor neurons are generated but do not acquire characteristic functional properties necessary for regulating muscle proprioception, thus disrupting gait and precision movements. Complementary gain-of-function experiments in chick suggest that ERR2 and ERR3 could operate via transcriptional activation of neural activity modulators to promote a gamma motor neuron biophysical signature of low firing thresholds and high firing rates. Our work identifies a mechanism specifying gamma motor neuron functional properties essential for the regulation of proprioceptive movement control.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Mice
  • Motor Neurons, Gamma* / physiology
  • Movement
  • Muscles
  • Proprioception
  • Receptors, Estrogen* / metabolism


  • Esrrb protein, mouse
  • Receptors, Estrogen
  • Esrrg protein, mouse

Grants and funding

This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, 368482240/GRK2416 to T.M.), the DFG Cluster of Excellence 171 for Nanoscale Microscopy and Molecular Physiology of the Brain, and European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement 311710-MU TUNING to T.M.). This work was also supported by BMBF IDSN, ERA-Net E-Rare MAXOMOD, and CRC 1286/Z2 (to S.B), European Research Council through the Synergy Grant NaturalBionicS (#810346 to D.F.) and the European Union’s Horizon 2020 research and innovation programme (Marie Skłodowska-Curie grant agreement No. 702491 (NeuralCon) to F.N.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.