Biology subjects

Mi, R.

Publications and source records attributed to Mi, R..

6 recordsLinked to original sources

bioRxiv2025

Lack of mRNA Methylation in Schwann Cells Results in Demyelination and Regenerative Failure

Schwann cells are essential for peripheral nerve myelination and regeneration. N6-methyladenosine (m6A) RNA methylation, regulated by methyltransferase-like 14 (Mettl14), is a critical post-transcriptional modification, but its role in Schwann cell biology remains unclear. Using a conditional knockout (cKO) mouse model, we investigated the impact of Mettl14-mediated m6A methylation on Schwann cells. Mice born with Schwann cell-specific genetic deletion of Mettl14 developed normally but starting in young adulthood exhibited progressive motor deficits, severe demyelination, and axonal degeneration, confirmed by behavioral assessments and histological analyses. Mettl14-deficient Schwann cells displayed impaired proliferation and mitochondrial dysfunction in vitro. Following sciatic nerve injury, Mettl14 cKO mice showed defective macrophage recruitment, slowed axonal degeneration, and impaired regeneration. These findings suggest that Mettl14-mediated m6A methylation is critical for Schwann cell maintenance but not development. Given that Mettl14 cKO mice developed a demyelinating polyneuropathy, it is possible that manipulation of m6A methylation in Schwann cells is a promising therapeutic strategy targeting peripheral nerve repair and myelination.

neuroscience↗

bioRxiv2025

Derived motor neurons transplantation promotes nerve regeneration in a rodent model of a chronically denervated nerve through delayed adoption of a chronic denervation phenotype

After acute injury, the peripheral nervous system regenerates more efficiently than the central nervous system, but this advantage is not maintained with chronic injuries. In large animals like humans, the slow rate of axon growth and the long distance between the central nervous system and end organ result in the adoption of a chronically denervated nerve phenotype even in the setting of acute injury: distal areas of the nerve become unable to support regenerating axons, even as the proximal aspect of the acute injury may be appropriately supportive of regeneration. We hypothesized that motor neuron transplantation into the denervated distal stump would maintain the regenerative capacity by effectively reducing the time and distance necessary for regeneration through relay formation as well as by supporting the host Schwann cells responsible for guiding regenerating axons. Using an in vitro assays, we showed the feasibility of relay formation by demonstrating ventral horn to derived-motor neuron synaptogenesis as identified by calcium imaging. Pilot studies of transplantation of embryonic stem cell-derived mouse motor neurons into chronically denervated rat nerves demonstrated improved regenerative capacity in the chronically denervated nerve following a delayed repair paradigm. While host to graft synaptogenesis was not observed, the Schwann cells in the transplanted nerve stump were maintained in a pro-regenerative state despite chronic denervation. These pilot data suggest cell transplantation can delay the adoption of a chronically denervated phenotype primarily by maintaining Schwann cells in a pro-regenerative state.

neuroscience↗

bioRxiv2024

Molecular Myelin Dysfunction in the Most Common Inherited Peripheral Neuropathies - CMT1A and HNPP

Charcot-Marie-Tooth Disease Type 1A (CMT1A) and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) are the most common inherited peripheral neuropathies and arise from copy number variation of the Peripheral Myelin Protein 22 gene (PMP22). While secondary axon degeneration has been proposed as a primary driver of pathogenesis, our prior work demonstrated neuromuscular deficits in CMT1A mice in the absence of overt axonal loss, prompting investigation into primary myelin dysfunction. Here, we reveal that altered PMP22 dosage profoundly disrupts molecular architecture at critical myelin subdomains, Schmidt-Lanterman incisures (SLIs) and Nodes of Ranvier. Using high-resolution confocal imaging of teased peripheral nerve fibers from CMT1A and HNPP model mice, we identified disorganization of adherens junctions, mislocalization of Connexin29, and altered distribution of nodal ion channels in CMT1A and HNPP, with several defects more pronounced in CMT1A, aligning with clinical severity. Notably, Kv1.2 and Caspr mislocalization along the internode and Nav nodal widening suggest disruption of axoglial domains essential for saltatory conduction. Together, these phenotypes support a model in which PMP22 governs myelin architecture, likely through adherens junction regulation, with its dysregulation predicted to impair metabolic support and axonal ion homeostasis, thereby compromising the structural and functional integrity of myelin and contributing directly to disease pathogenesis. These findings shift the pathogenic paradigm for CMT1A and HNPP from axonal degeneration to primary myelin failure and highlight actionable molecular targets for therapeutic intervention. This study offers mechanistic insight into CMT1A and HNPP and provides a conceptual framework with broad relevance to other dysmyelinating disorders. Main PointsO_LIPMP22 copy number variation disrupts myelin architecture at SLIs and Nodes of Ranvier. C_LIO_LIAdherens junction and axoglial domain defects are more severe in CMT1A than HNPP. C_LIO_LIFindings support primary myelin dysfunction as a key driver of pathogenesis. C_LI

neuroscience↗

bioRxiv2023

Stray cats and dogs carrying zoonotic Enterocytozoon bieneusi genotype D in China: a public health concern

Enterocytozoon bieneusi is reported to be a common microsporidian of humans and animals in various countries. However, scarce information on E. bieneusi has been recorded in cats (Felis catus) and dogs (Canis familiaris) in China. As such, we undertook molecular epidemiological investigation of E. bieneusi in cats and dogs in Shanghai, China. A total of 359 genomic DNAs were extracted from individual faecal samples from cats (n = 59) and dogs (n = 300), and then tested using a nested PCR-based sequencing approach employing internal transcribed spacer (ITS) of nuclear ribosomal DNA as the genetic marker. Enterocytozoon bieneusi was detected in 34 of all 359 (9.5%) faecal samples from cats (32.2%; 19/59) and dogs (5.0%; 15/300), including 24 stray cats and dogs (22.6%; 24/106), as well as ten household/raised cats and dogs (4.0%; 10/253). Correlation analyses revealed that E. bieneusi positive rates were significantly associated with stray cats and dogs (P < 0.05). The analysis of ITS sequence data revealed the presentation of five known genotypes CD7, CHN-HD2, D, PtEb IX and Type IV and two novel genotypes D-like1 and PtEb IX-like1. Zoonotic genotype D was the predominant type with percentage of 61.8 (21/34). Phylogenetic analysis of ITS sequence data sets showed that genotypes D, D-like1 and Type IV clustered within Group 1, showing zoonotic potential. The others were assigned into Group 10 with host specificity. These findings suggested that cats and dogs in Shanghai harbor zoonotic genotype D of E. bieneusi and may have a significant risk for zoonotic transmission. Further insight into the epidemiology of E. bieneusi in animals, water and the environment from other areas in China will be important to have an informed position on the public health significance of microsporidiosis caused by this microbe.

genetics↗

bioRxiv2021

Single-cell RNA-seq analysis reveals aberrant CSF1 expression in disease-causing synovial fibroblasts of pigmented villonodular synovitis

ObjectivesAlthough the role of the CSF1/CSF1R axis in pigmented villonodular synovitis (PVNS) has been confirmed, the cells that express CSF1 and CSF1R and the underlying mechanism remain unclear. Single-cell RNA sequencing (scRNA-seq) of PVNS obtained through biopsies depicted the cellular diversity of PVNS, revealed specific CSF1/CSF1R-expressing cells and further identified novel gene expression that is associated with the development of PVNS. MethodsscRNA-seq was performed on tissues obtained from the 6 biopsies of 3 patients with PVNS. Flow cytometry, immunofluorescence and western blot validated the transcriptional results, while co-culture systems revealed the cross talk between fibroblasts and macrophages. Results8 subsets of fibroblasts and 5 subsets of macrophages were identified from the synovium of patients with PVNS and were found to be related to distinct signaling pathways. The cellular components of localized and diffuse PVNS are overall similar. Moreover, the synovium and nodule of PVNS share similar composition. The specific cells expressing CSF1/CSF1R were also identified. Other than that, unique CXCL12+CSF1+ fibroblasts were revealed to attract macrophages as disease-causing synovial fibroblasts, leading to the formation of masses in PVNS. ConclusionsPVNS consists of macrophages, fibroblasts, T cells, endothelial cells and mast cells. Among them, the CSF1-expressing fibroblasts appeared to be tumor-like cells that attract macrophages, subsequently forming tumor-like mass in PVNS. This paves the path for novel treatments of PVNS by targeting CXCL12+CSF1+ fibroblasts and the CXCL12-CXCR4 axis.

molecular biology↗

bioRxiv2020

ATF6 aggravates angiogenesis-osteogenesis coupling during ankylosing spondylitis by mediating FGF2 expression in chondrocytes

Although angiogenesis-osteogenesis coupling is important in ankylosing spondylitis (AS), therapeutic agents targeting the vasculature remain elusive. Here, we identified activating transcription factor 6 (ATF6) as an important regulator of angiogenesis in AS patients. Firstly, we found that ATF6 and fibroblast growth factor 2 (FGF2) levels were higher in SKG mice and AS patient cartilage. The pro-angiogenic ability of human chondrocytes was enhanced through activated ATF6-FGF2 axis following long-term stimulation with inflammatory factors, e.g. TNF-, IFN-{gamma} or IL-17. Mechanistically, ATF6 interacted with the FGF2 promotor and promoted its transcription. Treatment with the ATF6 inhibitor Ceapin-A7 inhibited angiogenesis in vitro and angiogenesis-osteogenesis coupling in vivo. ATF6 may aggravate angiogenesis-osteogenesis coupling during AS by mediating FGF2 transcription in chondrocytes, implying that ATF6 represents a promising therapeutic target for AS.

molecular biology↗