Leucine-rich repeats containing 4 ( LRRC4 , also named netrin-G ligand 2 [NGL-2]) is a member of the NetrinGs ligands (NGLs) family. As a gene with relatively high and specific expression in brain, it is a member of the leucine-rich repeat superfamily and has been proven to be a suppressor gene for gliomas, thus being involved in gliomagenesis. LRRC4 is the core of microRNA-dependent multi-phase regulatory loops that inhibit the proliferation and invasion of glioblastoma (GB) cells, including LRRC4/NGL2-activator protein 2 (AP2)-microRNA (miR) 182-LRRC4 and LRRC4-miR185-DNA methyltransferase 1 (DNMT1)-LRRC4/specific protein 1 (SP1)-DNMT1-LRRC4. In this review, we demonstrated LRRC4 as a new member of the partitioning-defective protein (PAR) polarity complex that promotes axon differentiation, mediates the formation and plasticity of synapses, and assists information input to the hippocampus and storage of memory. As an important synapse regulator, aberrant expression of LRRC4 has been detected in autism, spinal injury and GBs. LRRC4 is a candidate susceptibility gene for autism and a neuro-protective factor in spinal nerve damage. In GBs, LRRC4 is a novel inhibitor of autophagy, and an inhibitor of protein-protein interactions involving in temozolomide resistance, tumor immune microenvironment, and formation of circular RNA.
Humans ; Cell Line, Tumor ; Glioblastoma/metabolism* ; Leucine ; Leucine-Rich Repeat Proteins/genetics* ; MicroRNAs ; Nerve Tissue Proteins/genetics* ; Tumor Microenvironment

OBJECTIVE: To explore the clinical and genetic characteristics of a child with Pallister-Hall syndrome (PHS). METHODS: DNA was extracted from peripheral blood sample from the child and subjected to whole exome sequencing. Suspected variants were verified by Sanger sequencing of his family members. RESULTS: Genetic testing revealed that the child has harbored a heterozygous c.3320_3330delGGTACGAGCAG (p.G1107Afs×18) variant of the GLI3 gene. Neither parent was found to carry the same variant. CONCLUSION The c.3320_3330delGGTACGAGCAG (p.G1107Afs×18) frameshift variant of the GLI3 gene probably underlay the pathogenesis of PHS in this child. Genetic testing should be considered for patients featuring hypothalamic hamartoma and central polydactyly.
Humans ; Child ; Pallister-Hall Syndrome/genetics* ; Kruppel-Like Transcription Factors/genetics* ; Zinc Finger Protein Gli3/genetics* ; Polydactyly/genetics* ; Hamartoma/pathology* ; Nerve Tissue Proteins/genetics*

OBJECTIVE: To explore the genetic basis for a child with Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities (NEDASB). METHODS: A child with NEDASB who presented at the Third Affiliated Hospital of Zhengzhou University in July 2021 was selected as the subject. Peripheral blood samples of the child and her parents were collected and subjected to high-throughput sequencing. Candidate variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: The child was found to harbor a heterozygous c.820_828delinsCTTCA (p.Thr274Leufs*121) variant of the NOVA2 gene, for which both of her parents were of wild type. The variant was predicted as pathogenic based on the guidelines from the American College of Medical Genetics and Genomics. CONCLUSION The heterozygous c.820_828delinsCTTCA (p.Thr274Leufs*121) variant of the NOVA2 gene probably underlay the disease in this child. Above finding has enriched the spectrum of NOVA2 gene variants and provided a basis for genetic counseling and prenatal diagnosis for this family.
Child ; Female ; Humans ; Pregnancy ; Autistic Disorder/genetics* ; Brain ; Computational Biology ; Genetic Counseling ; Mutation ; Nerve Tissue Proteins/genetics* ; Neuro-Oncological Ventral Antigen ; Neurodevelopmental Disorders ; RNA-Binding Proteins

Tongue squamous cell carcinoma is highly malignant and has a poor prognosis. In this study, we aimed to combine whole-genome sequencing, whole-genome methylation, and whole-transcriptome analyses to understand the molecular mechanisms of tongue squamous cell carcinoma better. Oral tongue squamous cell carcinoma and adjacent normal tissues from five patients with tongue squamous cell carcinoma were included as five paired samples. After multi-omics sequencing, differentially methylated intervals, methylated loop sites, methylated promoters, and transcripts were screened for variation in all paired samples. Correlations were analyzed to determine biological processes in tongue squamous cell carcinoma. We found five mutated methylation promoters that were significantly associated with mRNA and lncRNA expression levels. Functional annotation of these transcripts revealed their involvement in triggering the mitogen-activated protein kinase cascade, which is associated with cancer progression and the development of drug resistance during treatment. The prognostic signature models constructed based on WDR81 and HNRNPH1 and combined clinical phenotype-gene prognostic signature models showed high predictive efficacy and can be applied to predict patient prognostic risk in clinical settings. We identified biological processes in tongue squamous cell carcinoma that are initiated by mutations in the methylation promoter and are associated with the expression levels of specific mRNAs and lncRNAs. Collectively, changes in transcript levels affect the prognosis of tongue squamous cell carcinoma patients.
Humans ; Biomarkers, Tumor ; Nerve Tissue Proteins ; Prognosis ; Squamous Cell Carcinoma of Head and Neck/pathology* ; Tongue Neoplasms/pathology*

BACKGROUND: Exploring the underlying mechanism of rituximab resistance is critical to improve the outcomes of patients with diffuse large B-cell lymphoma (DLBCL). Here, we tried to identify the effects of the axon guidance factor semaphorin-3F (SEMA3F) on rituximab resistance as well as its therapeutic value in DLBCL. METHODS: The effects of SEMA3F on the treatment response to rituximab were investigated by gain- or loss-of-function experiments. The role of the Hippo pathway in SEMA3F-mediated activity was explored. A xenograft mouse model generated by SEMA3F knockdown in cells was used to evaluate rituximab sensitivity and combined therapeutic effects. The prognostic value of SEMA3F and TAZ (WW domain-containing transcription regulator protein 1) was examined in the Gene Expression Omnibus (GEO) database and human DLBCL specimens. RESULTS: We found that loss of SEMA3F was related to a poor prognosis in patients who received rituximab-based immunochemotherapy instead of chemotherapy regimen. Knockdown of SEMA3F significantly repressed the expression of CD20 and reduced the proapoptotic activity and complement-dependent cytotoxicity (CDC) activity induced by rituximab. We further demonstrated that the Hippo pathway was involved in the SEMA3F-mediated regulation of CD20. Knockdown of SEMA3F expression induced the nuclear accumulation of TAZ and inhibited CD20 transcriptional levels via direct binding of the transcription factor TEAD2 and the CD20 promoter. Moreover, in patients with DLBCL, SEMA3F expression was negatively correlated with TAZ, and patients with SEMA3F low TAZ high had a limited benefit from a rituximab-based strategy. Specifically, treatment of DLBCL cells with rituximab and a YAP/TAZ inhibitor showed promising therapeutic effects in vitro and in vivo . CONCLUSION Our study thus defined a previously unknown mechanism of SEMA3F-mediated rituximab resistance through TAZ activation in DLBCL and identified potential therapeutic targets in patients.
Humans ; Animals ; Mice ; Rituximab/therapeutic use* ; Hippo Signaling Pathway ; Lymphoma, Large B-Cell, Diffuse/pathology* ; Prognosis ; Semaphorins/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Membrane Proteins/genetics* ; Nerve Tissue Proteins/genetics*

Brain size abnormality is correlated with an increased frequency of autism spectrum disorder (ASD) in offspring. Genetic analysis indicates that heterozygous mutations of the WD repeat domain 62 (WDR62) are associated with ASD. However, biological evidence is still lacking. Our study showed that Wdr62 knockout (KO) led to reduced brain size with impaired learning and memory, as well as ASD-like behaviors in mice. Interestingly, Wdr62 Nex-cKO mice (depletion of WDR62 in differentiated neurons) had a largely normal brain size but with aberrant social interactions and repetitive behaviors. WDR62 regulated dendritic spinogenesis and excitatory synaptic transmission in cortical pyramidal neurons. Finally, we revealed that retinoic acid gavages significantly alleviated ASD-like behaviors in mice with WDR62 haploinsufficiency, probably by complementing the expression of ASD and synapse-related genes. Our findings provide a new perspective on the relationship between the microcephaly gene WDR62 and ASD etiology that will benefit clinical diagnosis and intervention of ASD.
Mice ; Animals ; Microcephaly/genetics* ; Autistic Disorder/metabolism* ; Autism Spectrum Disorder/metabolism* ; Nerve Tissue Proteins/metabolism* ; Brain/metabolism* ; Mice, Knockout ; Cell Cycle Proteins/metabolism*

The discovery of neuroglobin (Ngb), a brain- or neuron-specific member of the hemoglobin family, has revolutionized our understanding of brain oxygen metabolism. Currently, how Ngb plays such a role remains far from clear. Here, we report a novel mechanism by which Ngb might facilitate neuronal oxygenation upon hypoxia or anemia. We found that Ngb was present in, co-localized to, and co-migrated with mitochondria in the cell body and neurites of neurons. Hypoxia induced a sudden and prominent migration of Ngb towards the cytoplasmic membrane (CM) or cell surface in living neurons, and this was accompanied by the mitochondria. In vivo, hypotonic and anemic hypoxia induced a reversible Ngb migration toward the CM in cerebral cortical neurons in rat brains but did not alter the expression level of Ngb or its cytoplasm/mitochondria ratio. Knock-down of Ngb by RNA interference significantly diminished respiratory succinate dehydrogenase (SDH) and ATPase activity in neuronal N2a cells. Over-expression of Ngb enhanced SDH activity in N2a cells upon hypoxia. Mutation of Ngb at its oxygen-binding site (His⁶⁴) significantly increased SDH activity and reduced ATPase activity in N2a cells. Taken together, Ngb was physically and functionally linked to mitochondria. In response to an insufficient oxygen supply, Ngb migrated towards the source of oxygen to facilitate neuronal oxygenation. This novel mechanism of neuronal respiration provides new insights into the understanding and treatment of neurological diseases such as stroke and Alzheimer's disease and diseases that cause hypoxia in the brain such as anemia.
Rats ; Animals ; Neuroglobin/metabolism* ; Globins/metabolism* ; Nerve Tissue Proteins/metabolism* ; Neurons/metabolism* ; Hypoxia/metabolism* ; Brain/metabolism* ; Oxygen ; Anemia/metabolism* ; Adenosine Triphosphatases/metabolism*

The characteristic genetic abnormality of neuroendocrine neoplasms (NENs), a heterogeneous group of tumors found in various organs, remains to be identified. Here, based on the analysis of the splicing variants of an oncogene Focal Adhesion Kinase (FAK) in The Cancer Genome Atlas datasets that contain 9193 patients of 33 cancer subtypes, we found that Box 6/Box 7-containing FAK variants (FAK^6/7) were observed in 7 (87.5%) of 8 pancreatic neuroendocrine carcinomas and 20 (11.76%) of 170 pancreatic ductal adenocarcinomas (PDACs). We tested FAK variants in 157 tumor samples collected from Chinese patients with pancreatic tumors, and found that FAK^6/7 was positive in 34 (75.6%) of 45 pancreatic NENs, 19 (47.5%) of 40 pancreatic solid pseudopapillary neoplasms, and 2 (2.9%) of 69 PDACs. We further tested FAK splicing variants in breast neuroendocrine carcinoma (BrNECs), and found that FAK^6/7 was positive in 14 (93.3%) of 15 BrNECs but 0 in 23 non-NEC breast cancers. We explored the underlying mechanisms and found that a splicing factor serine/arginine repetitive matrix protein 4 (SRRM4) was overexpressed in FAK^6/7-positive pancreatic tumors and breast tumors, which promoted the formation of FAK^6/7 in cells. These results suggested that FAK^6/7 could be a biomarker of NENs and represent a potential therapeutic target for these orphan diseases.
Female ; Humans ; Alternative Splicing ; Breast Neoplasms/metabolism* ; Carcinoma, Pancreatic Ductal/pathology* ; Focal Adhesion Protein-Tyrosine Kinases/therapeutic use* ; Nerve Tissue Proteins/genetics* ; Neuroendocrine Tumors/genetics* ; Oncogenes ; Pancreatic Neoplasms/metabolism*

Humans ; Nerve Tissue Proteins ; Epithelial-Mesenchymal Transition/genetics* ; Constriction, Pathologic ; Receptors, Immunologic ; Epithelial Cells/metabolism* ; Smad3 Protein/metabolism* ; Transforming Growth Factor beta1/metabolism*

Artificial nerve guidance conduits (NGCs) are synthetic nerve grafts that are capable of providing the structural and nutritional support for nerve regeneration. The ideal NGCs have plenty of requirements on biocompatibility, mechanical strength, topological structure, and conductivity. Therefore, it is necessary to continuously improve the design of NGCs and establish a better therapeutic strategy for peripheral nerve injury in order to meet clinical needs. Although current NGCs have made certain process in the treatment of peripheral nerve injury, their nerve regeneration and functional outcomes on repairing long-distance nerve injury remain unsatisfactory. Herein, we review the nerve conduit design from four aspects, namely raw material selection, structural design, therapeutic factor loading and self-powered component integration. Moreover, we summarize the research progress of NGCs in the treatment of peripheral nerve injury, in order to facilitate the iterative updating and clinical transformation of NGCs.
Humans ; Peripheral Nerve Injuries/therapy* ; Guided Tissue Regeneration ; Nerve Regeneration/physiology* ; Sciatic Nerve