TGFb 1 Induces Axonal Outgrowth via ALK5/PKA/SMURF1-Mediated Degradation of RhoA and Stabilization of PAR6

ENEURO, 2020 · DOI: https://doi.org/10.1523/ENEURO.0104-20.2020 · Published: September 4, 2020

Simple Explanation

Transforming growth factor (TGF)b 1 has been linked to axon regeneration and recovery after CNS injury. This study found TGFb 1 upregulated in the stroke-denervated mouse spinal cord after ischemic injury to the motor cortex. The study investigates how TGFb 1 increases axonal sprouting and growth after cortical stroke. The signaling pathway involves ALK5 and SMAD3, and modulation of the cytoskeleton via PKA/SMURF1. Defining the downstream signaling pathway through which TGFb 1 induces neurite outgrowth may identify new therapeutic targets. This could increase compensatory sprouting and contribute to functional recovery.

Study Duration

4 weeks

Participants

21 adult C57BL/6J mice

Evidence Level

Not specified

Key Findings

1
TGFb 1 rescues neurite outgrowth under growth inhibitory conditions via the canonical TGFb R2/ALK5 signaling axis.
2
Protein kinase A (PKA)-mediated phosphorylation of the E3 ubiquitin ligase SMURF1 induces a switch of its substrate preference from PAR6 to the Ras homolog A (RhoA).
3
TGFb 1 enhances neurite outgrowth by downregulating RhoA, a downstream signaling mediator of many CNS-associated growth inhibitory molecules.

Research Summary

TGFb 1 mRNA is upregulated in the stroke-affected CST and iGM in the cervical spinal cord after a large stroke to the motor cortex, when compensatory axonal sprouting may be triggered. In vitro neurite outgrowth analysis showed TGFb 1 rescues neurite outgrowth through the canonical ALK5/SMAD3 signaling axis in a growth inhibitory environment. TGFb 1 leads to the accumulation of PAR6, and negatively impacts on the RhoA/ROCK pathway by reducing the SCE-induced accumulation of RhoA.

Practical Implications

Therapeutic Target Identification

The identification of the TGFb 1/ALK5/SMAD3 signaling pathway and its downstream effects on RhoA and PAR6 provides potential targets for therapeutic interventions to enhance structural plasticity and functional recovery after stroke.

Drug Development

The study suggests that prolonged treatment with TGFb 1 or a downstream effector of the TGFb 1/ALK5 signaling pathway may be used to enhance plasticity and extend its critical window after stroke.

Understanding Stroke Recovery

The results contribute to a better understanding of the molecular mechanisms underlying compensatory sprouting of re-innervating CSN axons in the stroke-denervated spinal cord.

Study Limitations

1
The study uses an in vitro model with the neuroblastoma-derived cell line N1E-115, which lacks the direct translational impact of primary cell cultures.
2
The study did not address effects on a transcriptional level, focusing instead on post-translational signaling mechanisms.
3
Systemic delivery of TGFb 1 would bring about unwanted negative side-effects owing to the plethora of functions of TGFb 1 as a inflammation related molecule.

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