DCC mediated axon guidance of spinal interneurons is essential for normal locomotor central pattern generator function

Abstract

Coordinated limb rhythmic movements take place through organized signaling in local spinal cord neuronal networks. The establishment of these circuitries during development is dependent on the correct guidance of axons to their targets. It has previously been shown that the well-known axon guidance molecule netrin-1 is required for configuring the circuitry that provides left-right alternating coordination in fictive locomotion. The attraction of commissural axons to the midline in response to netrin-1 has been shown to involve the netrin-1 receptor DCC (deleted in Colorectal Cancer). However, the role of DCC for the establishment of CPG coordination has not yet been resolved. We show that mice carrying a null mutation of DCC displayed an uncoordinated left-right activity during fictive locomotion accompanied by a loss of interneuronal subpopulations originating from commissural progenitors. Thus, DCC plays a crucial role in the formation of spinal neuronal circuitry coordinating left-right activities. Together with the previously published results from netrin-1 deficient mice, the data presented in this study suggest a role for the most ventral originating V3 interneurons in synchronous activities over the midline. Further, it provides evidence that axon crossing in the spinal cord is more intricately controlled than in previously suggested models of DCC-netrin-1 interaction.

Development and plasticity of commissural circuits: from locomotion to brain repair

“…Interestingly, in a hypomorphic DCC mutant, the 'kanga' mice, the CST projects bilaterally and hindlimbs move synchronously, which would support the current model [58]. However, in isolated spinal cord preparations, there is also a significant reduction of commissural projections from spinal cord CINs in DCC and Netrin-1 knockout mice, which could also account for the observed locomotor deficits [59,60] ( Figure 3B).…”

Functional Subpopulations of V3 Interneurons in the Mature Mouse Spinal Cord

“…Previous studies indicate that commissural V3 neurons function to establish stable gaits and synchronize outputs from the two halves of the spinal cord Rabe Bernhardt et al, 2012). We therefore asked whether two V3 subpopulations exhibiting unique properties played distinct roles in locomotion.…”

Commissural axonal corridors instruct neuronal migration in the mouse spinal cord

“…2 and Supplementary Fig. 2) [23][24][25][26]34,35 . Boc mutant embryos were similar to WT with a relatively mild (B5% previously reported widening) commissural defasciculation phenotype (Fig.…”