Axon-dependent expression of YAP/TAZ mediates Schwann cell remyelination but not proliferation after nerve injury

Abstract

1 2 YAP and TAZ are transcriptional regulators that powerfully stimulate cell proliferation, which 3 drives developmental or tumorigenic tissue growth. Previously we showed that YAP/TAZ 4 initiate and maintain Schwann cell (SC) differentiation, thereby forming and maintaining myelin 5 sheath around peripheral axons (Grove et al., 2017). Here we show that YAP/TAZ are required 6 for SCs to restore peripheral myelination after nerve injury. We find that YAP/TAZ dramatically 7 disappear from denervated, proliferating SCs of adult mice after peripheral nerve injury. They 8 reappear in SCs as axons regenerate. YAP/TAZ ablation does not impair SC proliferation or 9 transdifferentiation into growth promoting repair SCs. SCs lacking YAP/TAZ, however, fail to 10 upregulate myelin-associated genes and completely fail to remyelinate regenerated axons. We 11 also show that both YAP and TAZ are required for optimal remyelination. These findings 12 indicate that axons regulate transcriptional activity of YAP/TAZ in adult SCs and that YAP/TAZ 13

YAP and TAZ regulate Schwann cell proliferation and differentiation during peripheral nerve regeneration

“…These results confirm the important role of YAP and TAZ during remyelination observed in a recent study using the complete ablation of Yap and Taz (Grove et al, 2020); validating the use of the compound model Yap cHet ; Taz cKO to investigate the long‐term function of YAP and TAZ in remyelination. Since one copy of Yap is not enough to compensate for the lack of Taz , this suggests that similar to its role during SC development (Deng et al, 2017; Grove et al, 2017; Poitelon et al, 2016), Taz has a more prominent role in nerve repair compare to Yap (Grove et al, 2020). Finally, these data show that loss of YAP and TAZ expression, at least up to 60 dpi, induces a severe remyelination defect but does not constitute a complete block in peripheral nerve regeneration process.…”

“…Others and we showed that SCs lacking both YAP and TAZ are unable to proliferate properly and fail to myelinate developing peripheral nerves (Deng et al, 2017; Grove et al, 2017; Poitelon et al, 2016). Grove et al recently reported that YAP and TAZ are also essential for functional regeneration of peripheral nerves using inducible Yap and Taz double knockout in SC; Yap fl/fl; Taz fl/fl; Plp1 ‐cre ER (Grove et al, 2020). However, animals ablated for both Yap and Taz in adult myelinating SCs and oligodendrocytes exhibit severe weight loss, tremors, ataxia, and mortality within 2 weeks (Figure S1) (Deng et al, 2017; Grove et al, 2017), which prevents the assessment of the long‐term effect of YAP and TAZ loss required to make conclusions on their role in myelin maintenance and nerve regeneration after injury.…”

“…After peripheral nerve injury, YAP protein expression is not affected and analysis of Yap single‐knockout SCs suggests that YAP alone is not required for peripheral nerve repair and remyelination (Mindos et al, 2017). However, TAZ protein expression is upregulated similarly to c‐JUN (Mindos et al, 2017) and analysis of Taz single‐knockout in SCs show that absence of TAZ limits peripheral nerve remyelination (Grove, Lee, Zhao, & Son, 2020). Therefore, TAZ also plays a more important role than YAP in SC remyelination.…”

“…Therefore, TAZ also plays a more important role than YAP in SC remyelination. SCs lacking both YAP and TAZ ( Yap and Taz double‐knockout) wrap around regenerated axons normally but fail to differentiate into myelinating SCs to remyelinate axons (Grove et al, 2020). Surprisingly, absence of YAP and TAZ was shown to have no effect on the proliferation of repair SC and on the expression level of the key SC dedifferentiation marker c‐JUN (Grove et al, 2020).…”

“…SCs lacking both YAP and TAZ ( Yap and Taz double‐knockout) wrap around regenerated axons normally but fail to differentiate into myelinating SCs to remyelinate axons (Grove et al, 2020). Surprisingly, absence of YAP and TAZ was shown to have no effect on the proliferation of repair SC and on the expression level of the key SC dedifferentiation marker c‐JUN (Grove et al, 2020). Further, the role of YAP and TAZ in myelin maintenance is controversial due to conflicting reports, describing YAP and TAZ as being either essential or non‐essential for myelin maintenance when ablated in adult nerves (Deng et al, 2017; Grove et al, 2017).…”