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.
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Acknowledgements Thanks to S. Mikulovic and E. Restrepo for valuable input, C. Birchmeier for Lbx1 antibody, L. Enquist and J. Martin for PRV152, S. Ewart for horse samples, and B. Ågerup for access to race horses. The work was supported by grants from the Swedish Foundation for Strategic Research, the Swedish Research Council Formas (221-2009-1631), Swedish Research Council Medicine and Health (2007-3630/4479, 2010-4394), Swedish Society for Medical Research (H.W.), National Institute of Child Health & Human Development R01HD059862 (N.A.), and the Swedish Brain Foundation. Sequencing was performed by the SNP&SEQ Technology Platform, supported by Uppsala University and Hospital, SciLife Lab – Uppsala and the Swedish Research Council (80576801 and 70374401). Computer resources were supplied by UPPMAX. K.K. is a Royal Swedish Academy of Sciences Research Fellow supported by a grant from the Knut and Alice Wallenberg Foundation.