Heterozygous Dcc Mutant Mice Have a Subtle Locomotor Phenotype.

Louise Thiry,James P Fawcett,Julien Ferent,Ali Rastqar,Eric Beaumont,Frédéric Charron,Maxime Lemieux,Chloé Lemaire,Jimmy Peng,Robert M Brownstone,Marie Roussel,Frédéric Bretzner

doi:10.1523/eneuro.0216-18.2021

Abstract

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.

Highlights

Individuals carrying monoallelic DCC (Deleted in Colorectal Cancer) mutations exhibit congenital mirror movements, which are unintentional movements on one side of the body that are mirror reversals of intended unilateral movements on the opposite side (Schott and Syke, 1981; Srour et al, 2010)
We show that loss of one Dcc allele does not affect motor cortex, corticospinal efficacy, or skilled locomotor control in adult mice, but it increases flexor-related motoneuronal output in the developing spinal cord and increases duty cycle of the stance phase during treadmill locomotion at slow walking speeds in adult mice
This finding raises the possibility of the existence of subtle locomotor changes in humans carrying monoallelic DCC mutations

Summary

Introduction

Individuals carrying monoallelic DCC (Deleted in Colorectal Cancer) mutations exhibit congenital mirror movements, which are unintentional movements on one side of the body that are mirror reversals of intended unilateral movements on the opposite side (Schott and Syke, 1981; Srour et al, 2010). Bilateral motor responses can be evoked in response to unilateral transcranial magnetic stimulation of the motor cortex in these people (Srour et al, 2010; Welniarz et al, 2017) and, these bilateral motor responses are correlated with an abnormal bilateral projection of their corticospinal fibers at the level of the pyramidal decussation (Welniarz et al, 2017). This phenotype in DCC heterozygous humans is most likely a result of haplo-insufficiency, given that many of the mutations are predicted to result in mRNA degradation or truncated DCC proteins (Izzi and Charron, 2011; Peng and Charron, 2013). 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)

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