DOCK7 regulates WNT signaling and NMJ clustering in normal and DMD muscle

English, K. G.; Rorrer, S. N.; Karuppasamy, M.; Becker, K. A.; Crossman, D. K.; Lopez, M. A.; Thalacker-Mercer, A. E.; Alexander, M. S.

doi:10.64898/2025.12.23.696254

bioRxiv · 10.64898/2025.12.23.696254

DOCK7 regulates WNT signaling and NMJ clustering in normal and DMD muscle

English, K. G.·Rorrer, S. N.·Karuppasamy, M.·Becker, K. A.·Crossman, D. K.·Lopez, M. A.·Thalacker-Mercer, A. E.·Alexander, M. S.

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Abstract

Dedicator of cytokinesis (DOCK) proteins have diverse and critical roles in myoblast fusion, glucose metabolism, skeletal muscle regeneration, and neuronal polarity. DOCK7 is part of this 11-member family of atypical guanine exchange factors. While human DOCK7 pathogenic variants are rare, biallelic variants are known to result in hypotonia and ataxia in children. More recently, DOCK variants have been shown to impact disease pathogenesis as secondary modifiers. We used tissue-specific Dock7 conditional knockout mice to evaluate the roles of DOCK7 in the skeletal muscles and motor neurons. Both Dock7 knockout models developed significant nerve and muscle function deficits; however, the Dock7 motor neuron knockout mice showed more severe locomotor pathologies. RNA sequencing of the Dock7 knockout skeletal muscles revealed dysregulation of WNT signaling factors, and skeletal muscle repair and regeneration pathways. Molecular analysis revealed impaired DOCK7-mediated RAC1 activation that impacted acetylcholine receptor (AChR) clustering in both models. Interestingly, haploinsufficiency of Dock7 in mdx mice improved overall dystrophic muscle pathologies. We propose that DOCK7-RAC1 interactions result in activation of the WNT signaling pathway via the LRP4 receptor in the skeletal muscle and facilitate post-synaptic AChR clustering. Graphical AbstractDOCK7 is a regulator of normal and DMD muscle via the RAC1/WNT pathway. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/696254v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1ce84eaorg.highwire.dtl.DTLVardef@17855f1org.highwire.dtl.DTLVardef@15263d2org.highwire.dtl.DTLVardef@1778e0_HPS_FORMAT_FIGEXP M_FIG C_FIG

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English, K. G., Rorrer, S. N., Karuppasamy, M., Becker, K. A., Crossman, D. K., Lopez, M. A., Thalacker-Mercer, A. E., Alexander, M. S.. 2025-12-25. DOCK7 regulates WNT signaling and NMJ clustering in normal and DMD muscle. https://doi.org/10.64898/2025.12.23.696254

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