Abstract
Identifying 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 analyzed hop mice, which walk with a characteristic hopping gait using their hindlimbs in synchrony. Fictive locomotion experiments suggest that a local defect in the ventral spinal cord contributes to the aberrant locomotor phenotype. Hop mutant spinal cords had severe morphologic defects, including the absence of the ventral midline and a poorly defined border between white and gray matter. The hop mice represent the first model where, exclusively found in the lumbar domain, the left and right components of the central pattern generators (CPGs) are fused with a synchronous hindlimb gait as a functional consequence. These defects were associated with abnormal developmental processes, including a misplaced notochord and reduced induction of ventral progenitor domains. Whereas the underlying mutation in hop mice has been suggested to lie within the Ttc26 gene, other genes in close vicinity have been associated with gait defects. Mouse embryos carrying a CRISPR replicated point mutation within Ttc26 displayed an identical morphologic phenotype. Thus, our data suggest that the assembly of the lumbar CPG network is dependent on fully functional TTC26 protein.
Highlights
452 30 Results: 3560 Discussion: 1703 MoM: 2604 Figures: 7 Extended data figures: 6 AbstractIdentifying the spinal circuits controlling locomotion is critical for unravelling the 37 mechanisms controlling the production of gaits
Using CRISPR technology we introduced a single point mutation within the Tetratricopeptide repeat protein 26 (Ttc26) gene, which reproduced the anatomical phenotype observed in hop mice
The results showed that Netrin1 expression levels were severely reduced in the lumbar ventral spinal cord of hop mice, with a clear loss in the floorplate itself whereas remaining expression could be observed in the ventricular area
Summary
452 30 Results: 3560 Discussion: 1703 MoM: 2604 Figures: 7 Extended data figures: 6 AbstractIdentifying the spinal circuits controlling locomotion is critical for unravelling the 37 mechanisms controlling the production of gaits. The hop mice represent the first model where, exclusively found in the lumbar domain, the left and right components of the central pattern generators (CPGs) are fused with a synchronous hindlimb gait as a functional consequence These defects were associated with abnormal developmental processes, including a misplaced notochord and reduced induction of ventral progenitor domains. In the early 20th century, Thomas Graham-Brown demonstrated that the spinal cord could 66 generate the basic pattern for stepping without descending or peripheral input (Graham Brown T, 1911) Within his model of spinal locomotor control, he implemented Sherrington's term “half-center” for two groups of reciprocally organized neurons mutually inhibiting each other to provide a coordinated pattern for stepping. Mouse mutants with abnormal locomotor coordination have been informative for understanding CPG organization and function (Kullander et al, 2001, 2003; Lanuza et al, 2004; Akay et al, 2006; Lundfald et al, 2007; Crone et al, 2008, 2009; Zhang et al, 2008; Rabe et al, 2009; Zagoraiou et al, 2009; Restrepo et al, 2009; Andersson et al, 2012; Talpalar et al, 2013; Lemieux et al, 2016; Thiry et al, 2018).
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