Deletion of Calcineurin in Schwann Cells Does Not Affect Developmental Myelination, But Reduces Autophagy and Delays Myelin Clearance after Peripheral Nerve Injury

Abstract

In the PNS, myelination occurs postnatally when Schwann cells (SCs) contact axons. Axonal factors, such as Neuregulin-1 Type III, trigger promyelinating signals that upregulate myelin genes. Neuregulin-1 Type III has been proposed to activate calcineurin signaling in immature SCs to initiate differentiation and myelination. However, little is known about the role of calcineurin in promyelinating SCs after birth. By creating a SC conditional KO of calcineurin B (CnB scko), we assessed the effects of CnB ablation on peripheral myelination after birth in both male and female mice. Surprisingly, CnB scko mice have minimal myelination defects, no alteration of myelin thickness, and normal KROX20 expression. In contrast, we did find a unique role for calcineurin in SCs after nerve injury. Following nerve crush, CnB scko mice have slower degeneration of myelin compared with WT mice. Furthermore, absence of CnB in primary SCs delays clearance of myelin debris. SCs clear myelin via autophagy and recent literature has demonstrated that calcineurin can regulate autophagy via dephosphorylation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy. We demonstrate that loss of CnB reduces autophagic flux in primary SCs, indicating a possible mechanism for impaired myelin clearance. In addition, ablation of CnB impairs TFEB translocation to the nucleus 3 d after crush, suggesting that calcineurin may regulate autophagy in SCs via TFEB activation. Together, our data indicate that calcineurin is not essential for myelination but has a novel role in myelin clearance after injury.

Calcineurin Activity Is Increased in Charcot-Marie-Tooth 1B Demyelinating Neuropathy

“…4E,G). This is consistent with recent observations from our laboratory showing that KROX20 expression is independent of calcineurin activity in mature myelinating Schwann cells (Reed et al, 2020).…”

“…In immature Schwann cells, activation of calcineurin induces the expression of the promyelinating transcription factor Early Growth Response 2 (EGR2/ KROX20), thus representing an ideal candidate to be disrupted by P-PERK in a demyelinating neuropathy with an active UPR (Kao et al, 2009). However, our recent data have demonstrated that selective deletion of calcineurin in myelinating Schwann cells has no effect on KROX20 expression or myelin production, but rather limits myelin clearance after injury (Reed et al, 2020). We thus explored the hypothesis that P-PERK interacts and modulates calcineurin activity in S63del Schwann cells, thus contributing to the demyelinating neuropathy.…”

Lessons from Injury: How Nerve Injury Studies Reveal Basic Biological Mechanisms and Therapeutic Opportunities for Peripheral Nerve Diseases

“…Several studies, conducted first in zebrafish and later in mice, have shown that Schwann cells participate in the breakup of the axon during the process of axon degeneration [65][66][67][68][69][70]. This process involves the formation of constricting actomyosin spheres and partially requires placental growth factor signalling from the axon, the vascular endothelial growth factor receptor (VEGFR) on Schwann cells, activation of mechanistic target of rapamycin (mTOR) and potentially calcineurin B in Schwann cells [65,69,71,72]. Furthermore, it has recently been shown that Schwann cells upregulate glycolysis after injury and that this process may actually help to protect axons for a short period after injury prior to axon degeneration [65].…”

Multifaceted activities of transcription factor EB in cancer onset and progression

“…The role of TFEB in the modulation of cancer peripheral nervous system is mostly speculative. Of note, TFEB has been demonstrated to regulate the formation of myelin [141,142], which is instrumental in perineural invasion and tumor spread through this way [114,143].…”