Loss of Dcc in the spinal cord is sufficient to cause a deficit in lateralized motor control and the switch to a hopping gait

Peng, Jimmy; Ferent, Julien; Li, Qingyu; Liu, Mingwei; Silva, Ronan Vinicius Da; Zeilhofer, Hanns Ulrich; Kania, Artur; Zhang, Ying; Charron, Frédéric

doi:10.1002/dvdy.24549

Cited by 11 publications

(6 citation statements)

References 33 publications

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“…The absence of hopping in Shh::cre;Ntn1 lox/lox mice during treadmill locomotion demonstrates that corticospinal projections are not involved in the lateralization of motor control during automatic behaviors, in keeping with previous findings (Serradj et al, 2014). The hopping behavior, reported in Dcc Kanga mice carrying a spontaneous viable mutation in Dcc (Finger et al, 2002), is indeed caused by an impairment of the spinal circuitry (Peng et al, 2018).…”

Section: Discussionsupporting

confidence: 86%

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

et al. 2021

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Section: Discussionsupporting

confidence: 86%

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

et al. 2021

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“…In contrast to the hopping gait of Dcc kanga/kanga and Dcc kanga/mutant mice (Finger et al, 2002; or conditional ablation of Dcc in HoxB8-expressing spinal neurons (Peng et al, 2018), we found no defects in locomotor gait of adult Dcc +/-mice during treadmill locomotion. Although we only assessed Dcc +/mice at slow and intermediate walking speeds, no events of hop or gallop were observed during brief locomotor accelerations when the animals sped up to reach a locomotor frequency of 5-6 Hz.…”

Section: Increased Duration Of the Duty Cycle Of The Stance Phase Of ...contrasting

confidence: 91%

“…However, both neonatal Dcc -/and Dcc kanga/kanga spinal cords exhibit a robust reduction in the number of most commissural interneurons, including V0 and V3 commissural interneurons, thus leading to disorganization of the coupling between left and right locomotor activities (Rabe Bernhardt et al, 2012). More recently, it has been shown that a selective Dcc mutation in spinal interneurons (HoxB8 cre ; Dcc flox/and HoxB8 cre ; Dcc flox/flox ) exhibits a robust hopping phenotype in adult mice (Peng et al, 2018), indicating that local spinal cord defects following loss of Dcc cause a hopping gait.…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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Heterozygous Dcc Mutant Mice Have a Subtle Locomotor Phenotype

Thiry

Lemaire

Rastqar

et al. 2022

eNeuro

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Axon guidance receptors such as deleted in colorectal cancer (DCC) contribute to the normal formation of neural circuits, and their mutations can be associated with neural defects. In humans, heterozygous mutations in DCC have been linked to congenital mirror movements, which are involuntary movements on one side of the body that mirror voluntary movements of the opposite side. In mice, obvious hopping phenotypes have been reported for bi-allelic Dcc mutations, while heterozygous mutants have not been closely examined. We hypothesized that a detailed characterization of Dcc heterozygous mice may reveal impaired corticospinal and spinal functions. Anterograde tracing of the Dcc +/− motor cortex revealed a normally projecting corticospinal tract, intracortical microstimulation (ICMS) evoked normal contralateral motor responses, and behavioral tests showed normal skilled forelimb coordination. Gait analyses also showed a normal locomotor pattern and rhythm in adult Dcc +/− mice during treadmill locomotion, except for a decreased occurrence of out-of-phase walk and an increased duty cycle of the stance phase at slow walking speed. Neonatal isolated Dcc +/− spinal cords had normal left-right and flexor-extensor coupling, along with normal locomotor pattern and rhythm, except for an increase in the flexor-related motoneuronal output. Although Dcc +/− mice do not exhibit any obvious bilateral impairments like those in humans, they exhibit subtle motor deficits during neonatal and adult locomotion.

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“…The absence of hopping in Shh::cre;Ntn1 lox/lox mice during treadmill locomotion demonstrates that corticospinal projections are not involved in the lateralization of motor control during automatic behaviors, in keeping with previous findings 18 . The hopping behavior, reported in Dcc Kanga mice carrying a spontaneous viable mutation in Dcc 5 , is indeed caused by an impairment of the spinal circuitry 24 .…”

Section: Several Mechanisms Could Account For the Guidance Defect Of mentioning

confidence: 90%

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

Pourchet

Morel

Welniarz

et al. 2020

Preprint

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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.

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Loss of Dcc in the spinal cord is sufficient to cause a deficit in lateralized motor control and the switch to a hopping gait

Cited by 11 publications

References 33 publications

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

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

Heterozygous Dcc Mutant Mice Have a Subtle Locomotor Phenotype

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

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