Loss of floor plate Netrin-1 impairs midline crossing of corticospinal axons and leads to mirror movements

Abstract

Highlights d Depletion of floor plate Netrin-1 impairs midline crossing of corticospinal axons d Shh::cre;Ntn1 lox/lox mice have functional ipsilateral corticospinal projections d Lateralization of voluntary motor controls is selectively altered in these mice d These mice represent a model for human congenital mirror movements

Topography of corticopontine projections is controlled by postmitotic expression of the area-mapping gene Nr2f1

“…Compared to the Emx1-cKO mice, in which projections appear more disorganized and abundant, we considered the Nex-cKO mouse model, exhibiting externally shifted projections, more suitable for investigating the changes in topographical mapping using experimental tract tracing techniques. We injected the AAV9-CAGtdTomato anterograde viral tracer (Pourchet et al, 2021) in the cortex of 5 days-old (P5) Nex-cKO mice and littermate controls, in frontal and parietal locations corresponding to the motor or S1 areas in control mice, respectively ( Figures 6, 7 ). The mice were sacrificed at P21 and brain sections analysed microscopically ( Figure 1B ).…”

“…We therefore injected the AAV9-CAGtdTomato anterograde viral tracer (Pourchet et al, 2021) in motor, lateral or medial S1 cortex of 5 days-old (P5) Nex-cKO mice and littermate controls (Figures 6, 7). The mice were sacrificed at P21 and brain sections analyzed microscopically (Figure 1B In all control mice, the spatial distributions of corticopontine projections (dark gray point clouds in Figures 6 and 7) were comparable with the labelling patterns seen in corresponding wild-type tracing data from the Allen Mouse Brain Connectivity Atlas.…”

Heterozygous Dcc Mutant Mice Have a Subtle Locomotor Phenotype

“…Although the corticospinal tract and connectivity in the mouse are different from that of the human, previous studies using a spontaneous mutation allele that removes the exon encoding the P3 intracellular domain of DCC have shown that homozygous Dcc kanga/kanga and Dcc kanga/ − mice exhibit a hopping gait, ataxia, and abnormal pyramidal decussation through adulthood, thus recapitulating to some extent the motor phenotype of DCC haploinsufficient individuals ( Finger et al, 2002 ; Welniarz et al, 2017 ). We therefore examined Dcc heterozygous mice and assessed the contribution of Dcc to skilled motor and locomotor control, which relies on the integrity of the motor cortex and its corticospinal tract ( Pourchet et al, 2021 ). We found that Dcc +/− mice exhibited normal asymmetrical control of the forelimb during vertical exploration in the cylinder test; they also exhibited normal skilled forelimb coordination during voluntary locomotor control while walking on a wide and narrow beam and while crossing a horizontal ladder.…”

“…Mutations in NETRIN-1 also cause mirror movements in human ( Méneret et al, 2017 ). Loss of floor plate Netrin-1 in mice impairs midline crossing of corticospinal and spinal axons and leads to a bilateral forelimb movement phenotype reminiscent of human mirror movements ( Pourchet et al, 2021 ).…”

“…However, mutant mice carrying the bi-allelic kanga mutation ( Dcc kanga /kanga ), a spontaneous mutation that removes the P3 intracellular domain, are viable and exhibit an abnormal rabbit-like hopping gait ( Finger et al, 2002 ). The hopping gait phenotype is different from the bilateral forelimb movement phenotype: while the former is mostly known to occur because of axon crossing defects in spinal interneurons ( Kullander et al, 2003 ; Talpalar et al, 2013 ; Peng et al, 2018 ), the latter has been linked to crossing defects of the corticospinal tract ( Serradj et al, 2014 ; Pourchet et al, 2021 ). Corticospinal tract lateralization defects produce phenotypes more akin to the mirror-movement phenotype observed in DCC +/− humans.…”