Network analysis of potential targets of miR-449a-5p in axonal reconstruction after spinal cord injury

doi:10.21203/rs.3.rs-1606733/v1

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Network analysis of potential targets of miR-449a-5p in axonal reconstruction after spinal cord injury

https://doi.org/10.21203/rs.3.rs-1606733/v1

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Objective

To investigate the role of miR-449a-5p overexpressed in rats with spinal cord injury (SCI), and to predict the potential targets of miR-449a-5p by bioinformatic analysis and explore the underlying mechanism of the onset and development of axonal reconstruction in SCI.

Methods

Forty-eight SD female rats were randomly divided into Sham group, SCI group, agonist group (SCI + miR-449a-5p agomir), and agonist control group (SCI + agomir negative control).Basso-Beattie-Bresnahan (BBB) scores were performed after the successful establishment of SCI rat model. The targets of miR-449a-5p was searched in TargetSccan, miRDB, and miRWalk databases, and relevant literatures were retrieved in PubMed and CNKI using ‘miR-449a’ and ‘axonal regeneration’ as keywords, and genes not reported previously were subjected to Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analysis, and protein-protein interaction (PPI) network, and the hub genes were screened by Cytoscape.

Results

The BBB score results showed that the rats in SCI + miR-449a-5p agomir group exhibited gradual recovery after SCI surgery, with significant improvement compared to the SCI group. A total of 76 target genes of miR-449a-5p were obtained, and the hub genes were CNTN2, ANK3 and CNTNAP1.

Conclusions

The present study suggested that miR-449a-5p may participate in a variety of BP through target genes, and hub genes CNTN2, ANK3, and CNTNAP1 may provide help for the exploration of the mechanism of axonal reconstruction in SCI.

miR-449a-5p

spinal cord injury

axonal regeneration

bioinformatics

Spinal cord injury (SCI) is a severe central nervous system (CNS) injury, with various motor, sensory, and sphincter dysfunction, dystonia, and pathological reflexes observed in the corresponding segments of the lesion (Tator 1995, Zhou, Wang et al. 2016). Patients with SCI mostly show loss of function or even complete paralysis of the injured area, with a high disability rate. The sudden onset of SCI, the varying severity of the disease, and the difficulty of treatment and rehabilitation often leave different degrees of sensory, motor, and autonomic dysfunction, and patients have limited social participation, which will seriously affect the quality of life of patients and bring a heavy burden to individuals, families and society (Middleton, Dayton et al. 2012). In addition, the average life expectancy of SCI patients has been greatly extended, but the recovery process is long, accompanied by endless pain and suffering, and the quality of life is extremely poor. Therefore, it is of great clinical significance to find suitable therapeutic targets for spinal cord injury.

MicroRNA (miRNA) are small endogenous RNAs of approximately 20–24 nucleotides in length that bind to complementary binding sites of 3'-UTR of target mRNA. Inhibiting of mRNA translation or promotion of degradation plays an important regulatory role in spinal cord development, neuroplasticity, and pathological changes after injury (Strickland, Hook et al. 2011, Jee, Jung et al. 2012, Sambandan, Akbalik et al. 2017, Wang, Li et al. 2019). Intervention of miRNA expression is of great significance to alleviate secondary damage and improve neurological function in SCI, and may become an effective target for the treatment of SCI, providing new ideas, technologies and approaches for exploring clinical treatment of SCI and other diseases. At present, a large number of studies have found that miRNAs are closely related to the pathophysiological process of SCI. The miRNA-mediated pathophysiological responses play different roles in various stages of SCI, and can be simultaneously involved in multiple pathological processes after SCI by acting on different signaling pathways and targeted genes. Silencing of miR-324-5p alleviates the loss of motor ability in rats and mediates the degeneration of SCI pathogenesis through SIRT1 (Wang, Guo et al. 2021). Agomir-124 significantly inhibits neuronal reduction and astrocyte activation. TAL1 is a potential target gene of miR-124, and the low expression of this gene promotes proliferation and inhibits differentiation of neural progenitor cells. The miR-124/TAL1 axis may be involved in the treatment of SCI by agomir-124 through the regeneration of neural stem cells (Wang, Li et al. 2020). Loss of miR-155 enhanced neuronal expression of the injury-induced regeneration-related gene SPRR1A. The knockout of miR-155 mice reduced neuroinflammation in the spinal cord and increased peripheral conditioning outside the center pathologically enhanced axonal regeneration. However, the effect of miR-449a on axonal remodeling after SCI has not been reported.Therefore, it is of great clinical significance to find suitable therapeutic targets for spinal cord injury

This study is aimed to investigate the effect of miR-449a on axonal regeneration after SCI in rats and its possible mechanisms by increasing the level of miR-449a in the spinal cord through local injection of miR-449a-5p agonist, observing the changes in hind limb kinetic energy after agonist injection, and predicting the potential targets of miR-449a-5p by bioinformatics.

Animals and grouping

Forty-eight SD rats (female, aged 6-8 weeks, weighing 180-220g) were provided by the Department of Experimental Animals, Kunming Medical University (No. SCXK (Yunnan) K2020-0004), and were randomly divided into four groups, including Sham group (laminectomy only, n=12), SCI group (n=12), agonist group (SCI+miR-449a-5p agomir, n=12) and agonist control group (SCI+agomir NC, n=12). All procedures were approved by the Institutional Animal Care and Use Committee of Kunming Medical University (Approval No.KMMU20220859), and were accorded with Guide for the Care and Use of Laboratory Animals of National Institute of Health.

Establishment of spinal cord contusion model

The rats were anesthetized with 3% sodium pentobarbital (1 ml/kg) by intraperitoneal injection, and fixed in the prone position on a clean experimental table. A posterior midline incision of about 3cm was made with the T10 spinous process as the center, stripping the paravertebral muscles and exposing the T9-T11 spinous process and lamina. The interspinous ligament was cut and the T10 spinous process and lamina of T10 were dissected to expose an approximately 1-cm-long area centered on the T10 spinal segment. A 10 g metal rod was free-falling from a height of 2.5cm and impacted on the T10 nerve segment using a free-fall apparatus, followed by layer-by-layer suturing of muscle, subcutaneous tissue and skin. After the SCI model was successfully constructed, 20μl rno-miR-449a-5p agomir (100 μmol/L,) and agomir NC (100 μmol/L) were injected into the injured area of agonist group and agonist control group under a sterile environment. MiR-449a-5p agomir and agomir NC were synthesized by Ribobio (Guangzhou, China).Rats in Sham group underwent the same operation until the lamina was removed without SCI, and the wound was sutured as above. After surgery, all groups of rats were housed in cages and fed freely with standard chow and water. Sodium penicillin (8^*10⁴ U) was injected intramuscularly into the hind limbs once a day, and the surgical wound area was disinfected with iodophor twice a day for 3 consecutive days after surgery. The lower abdomen of the rats was massaged 3 times a day after surgery, and the bladder was gently pressed to help them urinate and defecate until the micturition reflex was restored.

Basso-Beattie-Bresnahan (BBB) scores

The BBB scores was performed on each group of rats at 1 days (d), 7 d, and 21 d after surgery to observe the motor ability and the recovery of each joint of the hind limb(Basso, Beattie et al. 1995).The BBB scores grade from 0 points (no obvious hind limb movement) to 21 points (normal activities). After SCI surgery,three experienced investigators performed the evaluation for 5 min of each animal, who were blinded to the group identity of the rats. The average score of three investigators was calculated as the final score for analysis.

Acquisition of gene targets

The gene targets of miR-499a-5p were searched from the TargetScan (http://www.targetscan.org/vert_71/), miRDB (http://mirdb.org/), and miRWalk (http://mirwalk.umm.uni-heidelberg.de/) databases. The species was set as ‘rat’, and the miRNA name was entered as miR-499a-5p. The intersected target genes were obtained from the intersection results of TargetScan, miRDB, and miRWalk databases using Venn (version 2.1.0, https://bioinfogp.cnb.csic.es/tools/ venny/index.html). In addition, the unreported intersected genes of miR-499a-5p and axonal regeneration were searched from PubMed and CNKI.

Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses

In this study, both Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways analyses using R language (version 3.6.0, http://www.r-project.org), and histograms and signaling pathway plots were plotted.

Protein-protein interaction (PPI) network analysis

The gene targets from Venny 2.1.0 were entered into the STRING database (https://string-db.org/), 'Organism' was selected as 'Rattus Norvegicus', and the results were exported and plotted using Cytoscape software (version 3.5.1, http://www. cytoscape.org) and the Cytohubba plugin to map the PPI network. Using Degree as the parameter criterion, regions in the PPI network were analyzed and the top 20 hub genes were screened by connectivity analysis.

Motor function assessment

As shown, the BBB scores of agonist group (SCI+miR-449a-5p agomir) was increased gradually and was significantly higher than that of SCI group (P<0.01, Figure 1), suggesting that the upregulation of miR-449a-5p significantly improved the recovery of motor function of rats with SCI.

Gene targets of miR-449a-5p

A total of 76 gene targets of miR-449a-5p were obtained from the intersection of results of TargetScan, miRWalk, and miRDB, as shown in Venn diagram (Table 1, Figure 2). However, no genes were reported to be associated with miR-449a-5p and axonal reconstruction.

Table 1. The 76 gene targets of miR-449a-5p.

Vamp2	Grem2	Nav3	Pacs1	Ttc19	Dpysl4	Dgkz	Mras
Pnoc	Ago4	Notch1	Sidt1	Sgsm2	Snx15	Areg	Tmem109
Flot2	Aff4	Klf4	Strn3	Asic2	Jakmip1	Shisa7	Mta2
Vat1	Cntn2	Ubp1	Cant1	Celf3	Capn5	Casp2	Bnc2
Zdhhc17	Ctnnd2	Sidt2	Itsn1	Zcchc17	Ralgds	Rras2	Rai14
Svop	Plod1	Mtmr14	Ltbp2	Ank3	Fbxo30	Gpr158	Cntnap1
Hdac1	Jag1	Ptpn4	Cacnb3	Kcnd3	Taf5	Stx17	Kitlg
Crhr1	Acsl1	Shoc2	Hecw2	Zfhx4	Synj1	Foxj2	Xpo5
Abr	Reln	Epn2	Nono	Ahcyl2	Wdr37	Usp24	Plcg1
Trim41	Zbtb20	Aldoa	Ppfia1

GO enrichment analysis

To explore the mechanism of miR-449a-5p on axonal regeneration after SCI, GO enrichment analysis was performed on the 76 gene targets of miR-449a-5p. It was found that the top 10 biological processes (BP) were involved in the regulation of ion transmembrane transport, protein localization to axon, synapse organization, response to muramyl dipeptide, regulation of cation transmembrane transport, regulation of ion transmembrane transporter activity, regulation of cation channel activity, regulation of transmembrane transporter activity, protein localization to plasma membrane, and regulation of transporter activity. The top 10 cell components (CC) were mainly as follows: synaptic membrane, anchored component of synaptic membrane, lamellipodium, cell leading edge, NuRD complex, node of Ranvier, CHD-type complex, fibrillar center, RISC complex, and RNAi effector complex. (Figure 3)

KEGG signaling pathways analysis

As shown, the 76 gene targets were enriched in Phospholipase D signaling pathway, Ras signaling pathway, and Phosphatidylinositol signaling system (Figure 4).

PPI network of 76 gene targets of miR-449a-5p

The first 20 hub genes were screened by PPI network analysis and then merged with the protein localization to axon in GO analysis to obtain the following hub genes: CNTN2, ANK3, and CNTNAP1

In the present study, we overexpressed miR-449a-5p in a rat model of SCI and used BBB scores to test the recovery and movement of rat hind limbs, as well as bioinformatics to analyze the potential targets of miR-449a-5p on axon regeneration after SCI. The 76 potential gene targets of miR-449a-5p were obtained from the databases, and were performed with GO enrichment analysis, and KEGG signaling pathways analysis, and PPI network. In GO enrichment analysis, regulation of ion transmembrane transport is the most abundant BP, and synaptic membrane is the most important chemical component in CC. Phospholipase D Signaling Pathway is the most important pathway in KEGG signaling pathway analysis, with the most significant differential expression, and we believe that miR-449a-5p may regulate the rehabilitation of axonal regeneration after SCI through this signaling pathway. PPI network analysis showed that CNTN2, ANK3 and CNTNAP1 were hug genes of miR-499a-5p.

SCI is a relatively common motor system injury in clinical practice, and its incidence is increasing year by year (Zhou, Wang et al. 2016, Eckert and Martin 2017). SCI results in varying degrees of paralysis or loss of work capacity in patients and are characterized by high morbidity, disability, and cost. SCI include primary and secondary injuries. Primary SCI is irreversible, while secondary SCI develops gradually after primary injuries and is often accompanied by axon demyelination, inflammation, apoptosis and glial scar formation, changes in gene expression and cellular metabolism, thus secondary SCI causes more severe damages to patients than primary SCI (Ratan and Noble 2009, Oyinbo 2011, Anwar, Al Shehabi et al. 2016, Cizkova, Murgoci et al. 2020).

As a kind of short non-coding single-stranded small molecule RNA in organisms, miRNA can regulate the expression of at least 30% of human protein-coding genes. More than 1000 miRNAs related to human beings have been identified, providing a new direction for the diagnosis, treatment and mechanism research of various clinical diseases (Shi, Zhou et al. 2017). MiR-449 family is located in the intron of cell division cycle gene 20B (CDC20B) on chromosome 5. This region has been identified as a strong cancer susceptibility site in earlier genome-wide association studies (Sucheston-Campbell, Clay-Gilmour et al. 2018). MiR-449a, located in the first intron of CDC20B on chromosome 5Q11, acts as a tumor suppressor by regulating cell proliferation, apoptosis, migration and invasion in a variety of cancers (Kumar, Sharad et al. 2016).

It was shown that TPD52 is a direct target of miR-449, and the expression of miR-449 was down-regulated and the expression of TPD52 was up-regulated in breast cancer cell line MDAMB-231, and it was speculated that the down-regulation of miR-449 may promote the migration and invasion of breast cancer cells by eliminating the inhibition of TPD52 (Zhang, Wang et al. 2017). Additionally, miR-449a acts as a tumor suppressor gene by suppressing the expression of CAPN6 or POU2F1 in hepatoma carcinomacells, inhibiting the proliferation of cancer cells, and promoting the apoptosis of HCC cells (Liu, Wang et al. 2016). Down-regulation of miR-449a-5p promotes the proliferation of esophageal squamous cell carcinoma cells, and silencing Bcl-2, a target gene of miR-449a-5p, reversed the effect of miR-449a-5p inhibitors on the proliferation of ECA-109 cells (Jiang, Zhao et al. 2020). It was shown that inhibition of miR-449a promotes cartilage regeneration and prevents osteoarthritis in an acute defect modelin vivo,intra-articular injection of LNA-anti-miR-449a prevents disease progression in osteoarthritis models (Baek, Lee et al. 2018). MiR-449a promotes neuron-like differentiation by targeting histone deacetylase 1 (HDAC1) expression (Liu, Hou et al. 2015). In this study, the rats exhibited the paralysis of hind limb and lost mobility after SCI modeling. Additionally, the comparison of BBB scores at 1d, 7d, and 21d after SCI surgery suggested that the overexpression of miR-499a-5p improved the recovery of motor function of rats with SCI. It is indicated that miR-449a-5p could induce or inhibit the repair process after SCI and change the rehabilitation process of SCI.

Biological function involved by gene targets of miR-499a-5p

In this study, the target genes of miR-449a-5p were predicted and GO analysis of target genes was carried out by bioinformatics. Protein localization to axonal and synaptic tissues were significantly enriched in BP related to axon regeneration. The axons of developing neurons produce an active structure called growth cone that guides their normal physiological processes. The growth cone regulates the growth, steering and localization of axons through continuous polymerization and depolymerization of microtubules and microfilaments. Tau is a microtubule-associated protein that is thought to be localized to axons. Moreover, Tau axon localization does not require stable microtubule binding. Tau lacks the microtubule binding domain (MTBD) and shows high diffusivity, but correctly localizes to axons (Iwata, Watanabe et al. 2019). The results of this study suggests that miR-449a may act mainly by interfering in the process of protein axonal localization.

Hub genes of miR-499a-5p

In this study, PPI network analysis of the predicted intersected gene targets of miR-499a-5p showed that HDAC1, Notch1 and Kitlg were centrally located and connected to many other nodes, and the hub genes CNTN2, ANK3 and CNTNAP1 were obtained from PPI network and GO enrichment analyses. CNTN2 is expressed in CNS and oligodendrocytes. CNTN2 in neurons is highly regulated during development and plays an important role in axon growth, guidance and neuronal migration. On the other hand, CNTN2 expressed in oligodendrocytes interferes with myelination, and its ablation leads to hypomyelination. It was found that CNTN2 in neurons may function through inhibition of Akt signaling pathway (Savvaki, Kafetzis et al. 2021). Also, the biological effect of miR-3075 on the phenotype of Schwann cells may be realized through the negative regulation of CNTN2, which regulates cell migration and myelination (Wang, He et al. 2018). The role of the ankyrin-G protein encoded by the ANK3 gene is to bind the skeleton protein to the cell membrane, and it plays an important role in many biological activities as an important linker protein. In recent years, it has been found that ankyrin-G proteins may be involved in signal transduction and apoptosis, and are involved in many key processes of signal transduction. The ANK3 gene,encoding multiple ankyrin-G subtypes, is widely expressed in various tissues, was first identified in the initial segment of axons and Ranferian node (Kordeli, Lambert et al. 1995), and is speculated to be involved in the process of axon reconstruction. CNTNAP1, also known as Caspr1, is a member of the Caspr family, and is involved in neural excitation and conduction and releases neurotransmitters in myelinated axons (Gollan, Salomon et al. 2003). Caspr1 is not only involved in the formation of myelinated axons, but also involved in maintenance the stability of adjacent connections, the formation, differentiation and proliferation of neurons and astrocytes, as well as motor control and cognitive functions (Sherman, Tait et al. 2005, Buttermore, Dupree et al. 2011). These results suggests that CNTN2, ANK3 and CNTNAP1 play an important role in neural repair during axonal regeneration and development after SCI.

The present study showed the overexpression of miR-499a-5p improve the recovery of motor function in rats with SCI. The hub genes CNTN2, ANK3 and CNTNAP1 of miR-499a-5p were obtained from the bioinformatics.

Acknowledgements

This article was supported by the General Project of Joint Special Fund for Applied Basic Research of Yunnan Provincial Science and Technology Department and Kunming Medical University, Project No. 2019FE001 (-025)

Conflict of interests

All authors declare that they have no conflict of interest in this article.

Author contributions

CW and TW designed the study, supervised the data collection, analyzed the data;NL interpreted the data and prepared the manuscript for publication; JS and JL undertaked animal experiments; QS reviewed the draft of the manuscript. All the authors have read and approved the manuscript.

Whether there is supporting data

I declare that the data and materials contained in this manuscript have not been published elsewhere and are available.

Ethical approval and consent for participation

All procedures were performed in accordance with the guidelines and approval of the Ethics Committee of the Kunming Medical University. Approved by the Animal Experiment Ethics Review Committee of Kunming Medical University, the approval number is KMMU20220859

Human and animal ethics

No human studies are involved

The animal ethics code is KMMU20220859

Public consent

I declare that all authors agree to publish.

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No competing interests reported.

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Network analysis of potential targets of miR-449a-5p in axonal reconstruction after spinal cord injury

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