Cell adhesion molecule L1 like plays a role in the pathogenesis of idiopathic hypogonadotropic hypogonadism

Chen, Yinwei; Sun, Taotao; Niu, Yonghua; Wang, D.; Liu, K.; Wang, T.; Wang, S.; Xu, Hao; Liu, J.

doi:10.1007/s40618-020-01485-1

Cited by 7 publications

(4 citation statements)

References 41 publications

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“…In L1-deficient mice, the size of the corpus callosum is reduced and callosal axons fail to cross the midline, 67 indicating that L1 contributes to the guidance of callosal axons. 64 Also, L1 acts in DNA repair, 68 is linked to hypogonadism, 69 and is involved in aging. 9,[70][71][72] In addition, the association of L1 with testicular germ cell tumors, 73 where HP1 functions, may indicate that L1 is needed for germ cells to develop normally.…”

Section: Discussionmentioning

confidence: 99%

Cell adhesion molecule L1 interacts with the chromo shadow domain of heterochromatin protein 1 isoforms α, β, and ɣ via its intracellular domain

et al. 2021

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Cell adhesion molecule L1 regulates multiple cell functions and L1 deficiency is linked to several neural diseases. Proteolytic processing generates functionally decisive L1 fragments, which are imported into the nucleus. By computational analysis, we found at L1's C‐terminal end the chromo shadow domain‐binding motif PxVxL, which directs the binding of nuclear proteins to the heterochromatin protein 1 (HP1) isoforms α, β, and ɣ. By enzyme‐linked immunosorbent assay, we show that the intracellular L1 domain binds to all HP1 isoforms. These interactions involve the HP1 chromo shadow domain and are mediated via the sequence 1158KDET1161 in the intracellular domain of murine L1, but not by L1's C‐terminal PxVxL motif. Immunoprecipitation using nuclear extracts from the brain and from cultured cerebellar and cortical neurons indicates that HP1 isoforms interact with a yet unknown nuclear L1 fragment of approximately 55 kDa (L1‐55), which carries ubiquitin residues. Proximity ligation indicates a close association between L1‐55 and the HP1 isoforms in neuronal nuclei. This association is reduced after the treatment of neurons with inhibitors of metalloproteases, β‐site of amyloid precursor protein cleaving enzyme (BACE1), or ɣ‐secretase, suggesting that cleavage of full‐length L1 by these proteases generates L1‐55. Reduction of HP1α, ‐β, or ‐ɣ expression by siRNA decreases L1‐dependent neurite outgrowth from cultured cortical neurons and decreases the L1‐dependent migration of L1‐transfected HEK293 cells in a scratch assay. These findings indicate that the interaction of the novel fragment L1‐55 with HP1 isoforms in nuclei affects L1‐dependent functions, such as neurite outgrowth and neuronal migration.

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Section: Discussionmentioning

confidence: 99%

Cell adhesion molecule L1 interacts with the chromo shadow domain of heterochromatin protein 1 isoforms α, β, and ɣ via its intracellular domain

et al. 2021

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“…Following the manufacturer’s instructions, we extracted RNA from purified sperm samples using RNA-easyTM Isolation Reagent (Vazyme, Nanjing, China) and synthesize cDNA using the Hifair ® II 1st Strand cDNA Synthesis Kit (Yeasen, Shanghai, China). Herein, we diluted the cDNA to the proper concentrations, and performed quantitative real-time polymerase chain reaction (qRT-PCR) as previously described ( 26 ). Expression levels of hub CORGs were calculated after normalization of the reference gene GAPDH .…”

Section: Methodsmentioning

confidence: 99%

Exploration of the common genetic landscape of COVID-19 and male infertility

et al. 2023

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BackgroundCOVID-19 has spread widely across continents since 2019, causing serious damage to human health. Accumulative research uncovered that SARS-CoV-2 poses a great threat to male fertility, and male infertility (MI) is a common comorbidity for the COVID-19 pandemic. The aim of the study was to explore the cross-talk molecular mechanisms between COVID-19 and MI.Materials and methodsA total of four transcriptome data regarding COVID-19 and MI were downloaded from the Gene Expression Omnibus (GEO) repository, and were divided for two purposes (initial analysis and external validation). Differentially expressed genes (DEGs) analysis, GO and pathway annotation, protein-protein interaction (PPI) network, connectivity ranking, ROC analysis, immune infiltration, and translational and post-translational interaction were performed to gain hub COVID-19-related DEGs (CORGs). Moreover, we recorded medical information of COVID-19 patients with MI and matched healthy controls, and harvested their sperm samples in the university hospital. Expressions of hub CORGs were detected through the qRT-PCR technique.ResultsWe identified 460 overlapped CORGs in both the COVID-19 DEGs and MI DEGs. CORGs were significantly enriched in DNA damage and repair-associated, cell cycle-associated, ubiquitination-associated, and coronavirus-associated signaling. Module assessment of PPI network revealed that enriched GO functions were closely related to cell cycle and DNA metabolism processes. Pharmacologic agent prediction displayed protein-drug interactions of ascorbic acid, biotin, caffeine, and L-cysteine with CORGs. After connectivity ranking and external validation, three hub CORGs (ENTPD6, CIB1, and EIF3B) showed good diagnostic performance (area under the curve > 0.75). Subsequently, three types of immune cells (CD8+ T cells, monocytes, and macrophages M0) were dominantly enriched, and 24 transcription factor-CORGs interactions and 13 miRNA-CORGs interactions were constructed in the network. Finally, qRT-PCR analysis confirmed that there were significant differences in the expression of hub CORGs (CIB1 and EIF3B) between the patient and control groups.ConclusionThe present study identified and validated hub CORGs in COVID-19 and MI, and systematically explored molecular interactions and regulatory features in various biological processes. Our data provide new insights into the novel biomarkers and potential therapeutic targets of COVID-19-associated MI.

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“…The detailed procedures of quantitative real-time polymerase chain reaction (qRT-PCR) were described previously (Chen et al, 2021). Then, primers were synthesized (Tsingke, Wuhan, China), and sequence information is shown in Supplementary Table S3.…”

Section: Mrna Measurement By Qrt-pcrmentioning

confidence: 99%

Identification of hub genes and biological mechanisms underlying the pathogenesis of asthenozoospermia and chronic epididymitis

Chen

Sun

et al. 2023

Front. Genet.

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Objective: Asthenozoospermia (AZS) is one of the most common causes of male fertility, affecting family wellbeing and population growth. Chronic epididymitis (CE) is a common and lingering inflammatory disease in the scrotum. Inflammation in the epididymis has a severe impact on sperm motility. This study aimed to explore the genetic profile and critical pathways involved in the pathological mechanisms of AZS and CE, and discover potential biomarkers.Methods: Genomic datasets of AZS and CE were obtained from the Gene Expression Omnibus (GEO) database, and relevant differentially expressed genes (DEGs) were identified. GO and pathway enrichment analyses, construction of a protein-protein interaction network, and receiver operator characteristic curve analysis were conducted. The expression profile of hub genes was validated in immunohistochemical data and testicular cell data. Immune infiltration, miRNA-hub gene interactions, and gene-disease interactions were explored. The mRNA levels of hub genes were further measured by qRT-PCR.Results: A total of 109 DEGs were identified between the AZS/CE and healthy control groups. Pathways of the immune system, neutrophil degranulation, and interleukin-4 and interleukin-13 signaling were enriched in AZS and CE. Five hub genes (CD300LB, CMKLR1, CCR4, B3GALT5, and CTSK) were selected, and their diagnostic values were validated in AZS, CE, and independent validation sets (area under the curve >0.7). Furthermore, the five-hub gene signature was well characterized in testicular immunohistochemical staining and testicular cells from healthy controls. Immune infiltration analysis showed that infiltration of CD8+ cells and T helper cells was significantly related to the expression level of five hub genes. In addition, a miRNA-hub gene network and interaction of other diseases were displayed. The mRNA levels of hub genes (CD300LB, CMKLR1, CCR4, and B3GALT5) were significantly elevated in the patient group. The mRNA level of CTSK also showed a similar trend.Conclusion: Our study uncovered the genetic profile involved in AZS and CE, and elucidated enriched pathways and molecular associations between hub genes and immune infiltration. This finding provides novel insight into the common pathogenesis of both diseases as well as the potential biomarkers for CE-associated AZS.

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Cell adhesion molecule L1 like plays a role in the pathogenesis of idiopathic hypogonadotropic hypogonadism

Cited by 7 publications

References 41 publications

Cell adhesion molecule L1 interacts with the chromo shadow domain of heterochromatin protein 1 isoforms α, β, and ɣ via its intracellular domain

Cell adhesion molecule L1 interacts with the chromo shadow domain of heterochromatin protein 1 isoforms α, β, and ɣ via its intracellular domain

Exploration of the common genetic landscape of COVID-19 and male infertility

Identification of hub genes and biological mechanisms underlying the pathogenesis of asthenozoospermia and chronic epididymitis

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