Abstract
The postinjury regenerative capacity of neurons is known to be mediated by a complex interaction of intrinsic regenerative pathways and external cues. In Caenorhabditis elegans, the initiation of axon regeneration is regulated by the nonmuscle myosin light chain-4 (MLC-4) phosphorylation signaling pathway. In this study, we have identified svh-16/cdk-14, a mammalian CDK14 homolog, as a positive regulator of axon regeneration in motor neurons. We then isolated the CDK-14-binding protein MIG-5/Disheveled (Dsh) and found that EGL-20/Wnt and the MIG-1/Frizzled receptor (Fz) are required for efficient axon regeneration. Further, we demonstrate that CDK-14 activates EPHX-1, the C. elegans homolog of the mammalian ephexin Rho-type GTPase guanine nucleotide exchange factor (GEF), in a kinase-independent manner. EPHX-1 functions as a GEF for the CDC-42 GTPase, inhibiting myosin phosphatase, which maintains MLC-4 phosphorylation. These results suggest that CDK14 activates the RhoGEF–CDC42–MLC phosphorylation axis in a noncanonical Wnt signaling pathway that promotes axon regeneration.SIGNIFICANCE STATEMENT Noncanonical Wnt signaling is mediated by Frizzled receptor (Fz), Disheveled (Dsh), Rho-type GTPase, and nonmuscle myosin light chain (MLC) phosphorylation. This study identified svh-16/cdk-14, which encodes a mammalian CDK14 homolog, as a regulator of axon regeneration in Caenorhabditis elegans motor neurons. We show that CDK-14 binds to MIG-5/Dsh, and that EGL-20/Wnt, MIG-1/Fz, and EPHX-1/RhoGEF are required for axon regeneration. The phosphorylation-mimetic MLC-4 suppressed axon regeneration defects in mig-1, cdk-14, and ephx-1 mutants. CDK-14 mediates kinase-independent activation of EPHX-1, which functions as a guanine nucleotide exchange factor for CDC-42 GTPase. Activated CDC-42 inactivates myosin phosphatase and thereby maintains MLC phosphorylation. Thus, the noncanonical Wnt signaling pathway controls axon regeneration via the CDK-14–EPHX-1–CDC-42–MLC phosphorylation axis.
Highlights
The ability of axons to regenerate after an injury is a fundamental and conserved property of neurons, governed by interactions between the intrinsic growth state and the extracellular microenvironment (Kaplan et al, 2015)
SVH-16/cyclin-dependent protein kinase-14 (CDK-14) is involved in axon regeneration So far, we have isolated 92 svh genes involved in axon regeneration (Li et al, 2012; Shimizu et al, 2018, 2021)
In the canonical Wnt signaling pathway, Wnt binds to the Frizzled receptor (Fz) receptor to activate the transcription of target genes through the regulation of b -catenin and T-cell factor (TCF)
Summary
The ability of axons to regenerate after an injury is a fundamental and conserved property of neurons, governed by interactions between the intrinsic growth state and the extracellular microenvironment (Kaplan et al, 2015). Neurons in the mammalian CNS have a limited regenerative capacity (Case and TessierLavigne, 2005). This difference in regenerative potential reflects alterations in the intrinsic capacity for axon growth. Understanding the intrinsic mechanisms that regulate axon regeneration provides insights into possible neurologic injuries and disease treatments. These intrinsic signaling mechanisms operating in the adult nervous system are not yet fully understood
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