Abstract
Mutations in RAD51 have recently been linked to human Congenital Mirror Movements (CMM), a developmental disorder of the motor system. The only gene previously linked to CMM encodes the Netrin-1 receptor DCC, which is important for formation of corticospinal and callosal axon tracts. Thus, we hypothesised that Rad51 has a novel role in Netrin-1-mediated axon development. In mouse primary motor cortex neurons, Rad51 protein was redistributed distally down the axon in response to Netrin-1, further suggesting a functional link between the two. We next manipulated Rad51 expression, and assessed Netrin-1 responsiveness. Rad51 siRNA knockdown exaggerated Netrin-1-mediated neurite branching and filopodia formation. RAD51 overexpression inhibited these responses, whereas overexpression of the CMM-linked R250Q mutation, a predicted loss-of-function, had no effect. Thus, Rad51 appears to negatively regulate Netrin-1 signalling. Finally, we examined whether Rad51 might operate by modulating the expression of the Unc5 family, known negative regulators of Netrin-1-responsiveness. Unc5b and Unc5c transcripts were downregulated in response to Rad51 knockdown, and upregulated with RAD51 overexpression, but not R250Q. Thus, Rad51 negatively regulates Netrin-1 signalling, at least in part, by modulating the expression of Unc5s. Imbalance of positive and negative influences is likely to lead to aberrant motor system development resulting in CMMs.
Highlights
Mutations in RAD51 have recently been linked to human Congenital Mirror Movements (CMM), a developmental disorder of the motor system
The shared CMM phenotype from mutations affecting either of these genes lead us to hypothesize that RAD51 may be involved in Netrin-1 signalling
Given that manipulation of Rad[51] expression impacted the branching of neurons in response to Netrin-1 in a manner that suggests it plays a role in opposing the stimulatory effects of Netrin-1 on neuritogenesis, we examined whether this might be due to alterations in the expression of Netrin-1 receptors
Summary
Mutations in RAD51 have recently been linked to human Congenital Mirror Movements (CMM), a developmental disorder of the motor system. Rad[51] is essential for proliferation; cells deficient in Rad[51] amass chromosomal abnormalities before eventual cell death[1], and genetic deletion is embryonic lethal in mice[3,4] Considering these known functions for maintaining DNA integrity, it was unanticipated when recent studies implicated mutations in RAD51 with both sporadic and familial cases of congenital mirror movements (CMM)[5,6,7]. Recording of scalp potentials during movement preparation, and interference with the cortical motor output by focal TMS, have shown bilateral activation of the motor cortex during intended movements, indicating abnormal callosal inter-hemispheric inhibition[10,11] These findings indicate that CMM are likely underpinned by abnormal development of the decussating CST and/or corpus callosum[11,12,13]. Rad[51] can be detected in the brain throughout development, and is expressed within neural progenitor cells in the developing mouse neocortex from as early as E12 through to post natal stages[6], it is unknown whether Rad[51] serves any additional cellular function outside of DNA repair
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