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

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Abstract
A premature stop codon in the DMRT3 gene has a major effect on the pattern of locomotion in horses, and the Dmrt3 transcription factor is critical in the development of a coordinated locomotor network in mice, suggesting that it has an important role in configuring the spinal circuits that control stride. Some horses — notably the harness-racing American Standardbred and the all-terrain Icelandic breed — have the ability to perform extra gaits. All horses can walk, trot, canter and gallop, but some can also 'pace' — moving the two legs on the same side of the body in unison — and/or perform other novel ambling gaits. A genome-wide association analysis of Icelandic horses has identified linkage between a premature stop codon in the DMRT3 gene and the ability to perform alternative gaits. Functional studies in mice show that Dmrt3 is expressed in a subset of spinal cord neurons that are crucial for the normal development of a coordinated locomotor network that controlling limb movements. Dmrt3 may therefore have a key role in configuring the spinal circuits that control stride in vertebrates. In the domestic horses, the DMRT3 mutation has had a major impact on the creatures' diversification, because the altered gait characteristics of a number of breeds apparently require this mutation. Locomotion in mammals relies on a central pattern-generating circuitry of spinal interneurons established during development that coordinates limb movement1. These networks produce left–right alternation of limbs as well as coordinated activation of flexor and extensor muscles2. 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.