Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice

TLDR

Locomotion in mammals relies on a central pattern‑generating spinal interneuron circuitry that coordinates limb movement and produces left‑right alternation and coordinated flexor/extensor activation. The study demonstrates that a premature stop codon in DMRT3 profoundly alters locomotion patterns in horses. In mice, Dmrt3 is expressed in the dI6 spinal cord subdivision, contributes to neuronal specification there, and is essential for normal development of a coordinated locomotor network controlling limb movements. The DMRT3 stop‑codon mutation permits alternate gaits, improves harness racing performance, and has driven diversification of domestic horse breeds by shaping stride‑controlling spinal circuits.

Abstract

Locomotion in mammals relies on a central pattern-generating circuitry of spinal interneurons established during development that coordinates limb movement. These networks produce left-right alternation of limbs as well as coordinated activation of flexor and extensor muscles. Here we show that a premature stop codon in the DMRT3 gene has a major effect on the pattern of locomotion in horses. The mutation is permissive for the ability to perform alternate gaits and has a favourable effect on harness racing performance. Examination of wild-type and Dmrt3-null mice demonstrates that Dmrt3 is expressed in the dI6 subdivision of spinal cord neurons, takes part in neuronal specification within this subdivision, and is critical for the normal development of a coordinated locomotor network controlling limb movements. Our discovery positions Dmrt3 in a pivotal role for configuring the spinal circuits controlling stride in vertebrates. The DMRT3 mutation has had a major effect on the diversification of the domestic horse, as the altered gait characteristics of a number of breeds apparently require this mutation.