A point mutation in Ttc26 causes lumbar spinal cord fusion and synchronous hind-limb locomotion in hop mice
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abstract
AbstractIdentifying the spinal circuits controlling locomotion is critical for unravelling the mechanisms controlling the production of gaits. Development of the circuits governing left-right coordination relies on axon guidance molecules such as ephrins and netrins. To date, no other class of proteins have been shown to play a role during this process. Here we have analyzedhopmice, which walk with a characteristic hopping gait using their hind legs in synchrony. Fictive locomotion experiments suggest that a local defect in the ventral spinal cord contributes to the aberrant locomotor phenotype.Hopmutant spinal cords had severe morphological defects, including the absence of the ventral midline and a poorly defined border between white and grey matter. Thehopmice represent the first model where the left and right central pattern generators (CPGs) are fused to form one central CPG, with a synchronous gait as a functional consequence. These defects were exclusively found in the lumbar domain and were associated with abnormal developmental processes, including a misplaced notochord and reduced induction of ventral progenitor domains. While the underlying mutation inhopmice has been suggested to lie withinTtc26, other genes in close vicinity have been associated with gait defects. By replicating the point mutation withinTtc26, employing CRISPR technology, we observed mice with an identical phenotype, thereby verifying the hop mutation. Thus, we show that the assembly of the lumbar CPG network is dependent on a fully functional TTC26 protein.
