Specific labeling of synaptic schwann cells reveals unique cellular and molecular features

Castro, Ryan; Taetzsch, Thomas; Vaughan, Sydney K.; Godbe, Kerilyn N.; Chappell, John C.; Settlage, Robert E.; Valdez, Gregorio

doi:10.7554/elife.56935

Cited by 47 publications

(47 citation statements)

References 98 publications

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“…NG2 has previously been shown to be co-expressed with S100 in mouse tSCs. 21 Similar to previous reports from rodents, we found that S100 and NG2 were co-expressed at human tSCs ( Fig. 4 ).…”

Section: Resultssupporting

confidence: 91%

Terminal Schwann cells at the human neuromuscular junction

Alhindi

Boehm

Forsythe

et al. 2021

Brain Communications

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Terminal Schwann cells are non-myelinating glial cells localised to the neuromuscular junction. They play an important role in regulating many aspects of neuromuscular junction form and function, in health and during disease. However, almost all previous studies of mammalian terminal Schwann cells have used rodent models. Despite a growing awareness of differences in the cellular and molecular anatomy of rodent and human neuromuscular junctions, it remains unclear as to whether these differences also extend to the terminal Schwann cells. Here, we have adapted immunohistochemical protocols to facilitate visualisation and comparative morphometric analyses of terminal Schwann cells at the human and mouse neuromuscular junction. We labelled terminal Schwann cells in the peroneus brevis muscle in six adult mice and five humans with antibodies against S100 protein. All human neuromuscular junctions were associated with at least one terminal Schwann cell, consistent with findings from other species, with an average of ∼1.7 terminal Schwann cells per neuromuscular junction in both humans and mice. In contrast, human terminal Schwann cells were significantly smaller than those of mice (p ≤ 0.01), in keeping with differences in overall synaptic size. Human terminal Schwann cell cytoplasm extended significantly beyond the synaptic boundaries of the neuromuscular junction, whereas terminal Schwann cells in mice were largely restricted to the synapse. Moreover, there was a significant difference in the location of terminal Schwann cell nuclei (p ≤ 0.01), with human terminal Schwann cells having their nuclear compartment located beyond the perimeter of the synapse more than the mouse. Taken together, these findings demonstrate that terminal Schwann cells at the human neuromuscular junction have notable differences in their morphology and synaptic relationships compared to mice. These fundamental differences need to be considered when translating the findings of both neuromuscular junction biology and pathology from rodents to humans.

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Section: Resultssupporting

confidence: 91%

Terminal Schwann cells at the human neuromuscular junction

Alhindi

Boehm

Forsythe

et al. 2021

Brain Communications

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“…At 7 dpc, muscles were isolated and stained for NMJs. We found that each NMJ was covered by 2~4 tSCs, consistent with the tSC number under normal conditions (Figure 4A) [31,32]. In addition, the average tSC numbers, NMJ tSCs distribution, and tSC soma areas did not differ between the Dhh-tdTomato and Dhh-tdTomato-Lrp4 −/− mice (Figure 4B-D).…”

Section: The Mscs Rather Than Tscs Are Involved In Accelerating Nerve Regeneration In Lrp4 Cko Micesupporting

confidence: 77%

Ablation of Lrp4 in Schwann Cells Promotes Peripheral Nerve Regeneration in Mice

Tao

Lai

Dong

et al. 2021

Biology

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Low-density lipoprotein receptor-related protein 4 (Lrp4) is a critical protein involved in the Agrin-Lrp4-MuSK signaling pathway that drives the clustering of acetylcholine receptors (AChRs) at the neuromuscular junction (NMJ). Many studies have shown that Lrp4 also functions in kidney development, bone formation, nervous system development, etc. However, whether Lrp4 participates in nerve regeneration in mammals remains unknown. Herein, we show that Lrp4 is expressed in SCs and that conditional knockout (cKO) of Lrp4 in SCs promotes peripheral nerve regeneration. In Lrp4 cKO mice, the demyelination of SCs was accelerated, and the proliferation of SCs was increased in the injured nerve. Furthermore, we identified that two myelination-related genes, Krox-20 and Mpz, were downregulated more dramatically in the cKO group than in the control group. Our results elucidate a novel role of Lrp4 in peripheral nerve regeneration and thereby provide a potential therapeutic target for peripheral nerve recovery.

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“…The data from this project combined with those from Castro et al (2020) will enhance tSC investigation. 15 Seemingly incongruous to this dearth of work is the importance of tSC functions, particularly their roles in NMJ reinnervation after motor nerve injury. 9,10,24 Although we have demonstrated the expression of TBX21 in tSCs, further work needs to be conducted to investigate its function within tSCs.…”

Section: Discussionmentioning

confidence: 99%

“…Castro et al recently identified neuron-glia antigen 2 a unique marker of differentiated tSCs using RNA seq. 15 In this study, we propose the T-box transcription factor 21 (TBX21 or T-BET) is expressed in tSCs at the NMJ in mice. This finding will augment the investigative tools available to modulate these cells to propel tSC investigation and enhance our understanding of these cells to better promote motor recovery after nerve injury.…”

Section: Introductionmentioning

confidence: 97%

T‐box transcription factor 21 is expressed in terminal Schwann cells at the neuromuscular junction

et al. 2021

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Introduction/Aims: Terminal Schwann cells (tSCs) are nonmyelinating Schwann cells present at the neuromuscular junction (NMJ) with multiple integral roles throughout their lifespan. There is no known gene differentiating tSCs from myelinating Schwann cells, making their isolation and investigation challenging. In this work we investigated genes expressed within tSCs.Methods: A novel dissection technique was utilized to isolate the tSC-containing NMJ band from the sternomastoid muscles of S100-GFP mice. RNA was isolated from samples containing: (a) NMJ bands (tSCs with nerve and muscle), (b) nerve, and (c) muscle, and microarray genetic expression analysis was conducted. Data were validated by quantitative real-time polymerase chain reaction (qRT-PCR) and immunofluorescent staining. To identify genes specific to tSCs compared with other NMJ components, analysis of variance and rank-order analysis were performed using the Partek Genomic Suite.Results: Microarray analysis of the tSC-enriched NMJ band revealed upregulation (by 4-to 12-fold) of several genes unique to the NMJ compared with muscle or nerve parts alone (P < .05). Among these genes, Tbx21 (or T-bet) was identified, which showed a 12-fold higher expression at the NMJ compared with sciatic nerve (P < .002). qRT-PCR analysis showed Tbx21 mRNA expression was over ninefold higher (P < .05) in the NMJ relative to muscle and nerve. Tbx21 protein colocalized with tSCs and was not noted in myelinating SCs from sciatic nerve.Discussion: We found TBX21 to be expressed in tSCs. Additional studies will be performed to determine the functional significance of TBX21 in tSCs. These studies may enhance the investigative tools available to modulate tSCs to improve motor recovery after nerve injury.

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Specific labeling of synaptic schwann cells reveals unique cellular and molecular features

Cited by 47 publications

References 98 publications

Terminal Schwann cells at the human neuromuscular junction

Terminal Schwann cells at the human neuromuscular junction

Ablation of Lrp4 in Schwann Cells Promotes Peripheral Nerve Regeneration in Mice

T‐box transcription factor 21 is expressed in terminal Schwann cells at the neuromuscular junction

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