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

Abstract

In human, execution of unimanual movements requires lateralized activation of the primary motor cortex, which then transmits the motor command to the contralateral hand through the crossed corticospinal tract (CST). Mutations in NETRIN-1 alter motor control lateralization, leading to congenital mirror movements. To address the role of midline Netrin-1 on CST development and subsequent motor control, we analyzed the morphological and functional consequences of floor-plate Netrin-1 depletion in conditional knock-out mice (Shh::cre;Ntn1 lox/lox mice). Here, we show that depletion of floor plate Netrin-1 critically disrupts midline crossing of the CST, whereas the other commissural systems are mostly preserved. The CST defect results in abnormal but functional ipsilateral projections, and is associated with abnormal symmetric movements. Therefore, our study reveals a new role for Netrin-1 in CST development. It also describes a unique mouse model recapitulating characteristics of human congenital mirror movements, through abnormal CST decussation.

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

“…In addition to Nr2f1 gradient expression in cortical progenitors and early postmitotic neurons, high expression in primary sensory areas, in which different sensory surfaces are topographically organized, is maintained at postnatal stages and still consistent with a high caudolateral to low anteromedial gradient ( Figure 7A ). To further and directly support our hypothesis of a cortical influence in topographical pontine mapping, we 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 ( Figure 7B ). The mice were sacrificed at P21 and brain sections analyzed microscopically.…”

Netrin-1 receptor DCC is required for the contralateral topography of lamina I anterolateral system neurons

“… 23 , 45 , 52 , 78 , 82 Developmental perturbations of Netrin-1:DCC signalling result in abnormal motor behaviour in mice and humans, presumably caused by decreased midline crossing by spinal interneurons and corticospinal axons. 63 , 64 , 73 However, the role of Netrin-1:DCC signalling in AS neuron development and function is only beginning to emerge. Loss of embryonic DCC expression in the caudal spinal cord ( Dcc spinal knockout; Dcc SpKO ) results in increased ipsilateral innervation of the thalamus by spinothalamic (ST) neurons and inability to accurately localize noxious stimuli.…”