Background: Dedicator of cytokinesis (DOCK) proteins have critical roles in myoblast fusion, glucose metabolism, skeletal muscle regeneration, and neuronal polarity. Previously, we demonstrated that DOCK3 is a dosage-sensitive modifier of Duchenne muscular dystrophy (DMD) pathologies as DOCK3 expression was induced in response to dystrophic disease progression. Following a similar expression pattern to DOCK3, DOCK7 expression is upregulated in both human DMD muscle and multiple DMD mouse models. DOCK7 primarily activates a RAC1 signaling cascade that functions to modulate cytoskeletal actin-filament polymerization and organization. DOCK7 deficiency leads to hypotonia and ataxia.
Hypothesis: We hypothesized that DOCK7 plays an integral role as a modifier of neuromuscular health and function through its activation of RAC1 signaling. Additionally, impaired muscle function due to Dock7 deficiency, modeled with Dock7 conditional knockout (KO) mice, can be ameliorated by constitutive skeletal muscle RAC1 activation.
Methods: We generated Dock7 muscle KO mice (Dock7 mKO) and Dock7 motor neuron KO (Dock7 mnKO) by mating our Dock7 flox/flox conditional mice with HSA-Cre (mKO; myofiber knockout) transgenic and vChAT-Cre (mnKO; motor neuron knockout) transgenic mice. We performed systemic evaluation of the Dock7 mKO and mnKO mouse histology, muscle performance, molecular transcriptomes, and overall function. We will further assess molecular pathway activation using RNA-sequencing.
Results: Dock7 mKO mice have impaired grip strength, locomotive activity, muscle architecture, and overall muscle deficits compared to WT controls. Dock7 knockout muscle also has impaired RAC1 pathway dynamics. Preliminary data indicates Dock7 mnKO mice have more severe neuromuscular deficits than the Dock7 mKO mice. Utilizing both tissue-specific KO models allows us to assess the contributions of DOCK7 protein in each system independently.
Conclusions: DOCK7 is essential for normal neuromuscular function, structure, and overall performance. Genetic disruption of the DOCK7-RAC1 protein-protein interaction results in RAC1 pathway disruption and a failure to properly activate RAC1 in Dock7-deficient tissue.