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Extracellular matrix (ECM) deposition after central nervous system (CNS) injury leads to inhibitory scarring in humans and other mammals, whereas it facilitates axon regeneration in the zebrafish. However, the molecular basis of these different fates is not understood. Here, we identify small leucine-rich proteoglycans (SLRPs) as a contributing factor to regeneration failure in mammals. We demonstrate that the SLRPs chondroadherin, fibromodulin, lumican, and prolargin are enriched in rodent and human but not zebrafish CNS lesions. Targeting SLRPs to the zebrafish injury ECM inhibits axon regeneration and functional recovery. Mechanistically, we find that SLRPs confer mechano-structural properties to the lesion environment that are adverse to axon growth. Our study reveals SLRPs as inhibitory ECM factors that impair axon regeneration by modifying tissue mechanics and structure, and identifies their enrichment as a feature of human brain and spinal cord lesions. These findings imply that SLRPs may be targets for therapeutic strategies to promote CNS regeneration., (© 2023. The Author(s).)

Maternal care is critical for epigenetic programming during postnatal brain development. Stress is recognized as a critical factor that may affect maternal behavior, yet owing to high heterogeneity in stress response, its impact varies among individuals. We aimed here to understand the connection between inborn stress vulnerability, maternal care, and early epigenetic programming using mouse populations that exhibit opposite poles of the behavioral spectrum (social dominance [Dom] and submissiveness [Sub]) and differential response to stress. In contrast to stress-resilient Dom dams, stress-vulnerable Sub dams exhibit significantly lower maternal attachment, serum oxytocin, and colonic Lactobacillus reuteri populations. Sub offspring showed a reduced hippocampal expression of key methylation genes at postnatal day (PND) 7 and a lack of developmentally-dependent increase in 5-methylcytosine (5-mC) at PND 21. In addition, Sub pups exhibit significant hypermethylation of gene promoters connected with glutamatergic synapses and behavioral responses. We were able to reverse the submissive endophenotype through cross-fostering Sub pups with Dom dams (Sub/D). Thus, Sub/D pups exhibited elevated hippocampal expression of DNMT3A at PND 7 and increased 5-mC levels at PND 21. Furthermore, adult Sub/D offspring exhibited increased sociability, social dominance, and hippocampal glutamate and monoamine levels resembling the neurochemical profile of Dom mice. We postulate that maternal inborn stress vulnerability governs epigenetic patterning sculpted by maternal care and intestinal microbiome diversity during early developmental stages and shapes the array of gene expression patterns that may dictate neuronal architecture with a long-lasting impact on stress sensitivity and the social behavior of offspring., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Our pilot study aimed at exploratory radiogenomic data analysis in patients with NF2-associated schwannomatosis (formerly neurofibromatosis type II) to assume the potential of image biomarkers in this pathology. Fifty-three unrelated patients (37 (69.8%) women, avg. age 30.2 ± 11.2 y.o.) were enrolled in the study. First-order, gray-level co-occurrence matrix (GLCM), gray-level run length matrix (GLRLM), and geometry-based statistics were calculated (3718 features per region of interest). We demonstrated imaging patterns and statistically significant differences in radiomic features potentially related to the genotype and clinical phenotype of the disease. However, the clinical utility of these patterns should be further evaluated. The study was supported by the Russian Science Foundation grant 21-15-00262.

Patients with tuberous sclerosis complex present with cognitive, behavioral, and psychiatric impairments, such as intellectual disabilities, autism spectrum disorders, and drug-resistant epilepsy. It has been shown that these disorders are associated with the presence of cortical tubers. Tuberous sclerosis complex results from inactivating mutations in the TSC1 or TSC2 genes, resulting in hyperactivation of the mTOR signaling pathway, which regulates cell growth, proliferation, survival, and autophagy. TSC1 and TSC2 are classified as tumor suppressor genes and function according to Knudson's two-hit hypothesis, which requires both alleles to be damaged for tumor formation. However, a second-hit mutation is a rare event in cortical tubers. This suggests that the molecular mechanism of cortical tuber formation may be more complicated and requires further research. This review highlights the issues of molecular genetics and genotype-phenotype correlations, considers histopathological characteristics and the mechanism of morphogenesis of cortical tubers, and also presents data on the relationship between these formations and the development of neurological manifestations, as well as treatment options.

Meningioma is the most common primary tumor of the central nervous system. Traditional classification is based on histological properties of tumors and distinguishes different grades of meningioma malignancy. However, knowledge about different molecular mechanisms of tumor provided new data on genetic features of meningiomas. The authors analyze current available data on the main driver mutations, new classifications based on molecular genetic characteristics and potential targets for therapy.

Chordoma associated with tuberous sclerosis complex (TSC) is an extremely rare tumor that was described only in 13 cases since 1975. Сhordoma itself is a malignant slow-growing bone tumor thought to arise from vestigial or ectopic notochordal tissue. Chordoma associated with TSC differs from chordoma in the general pediatric population in the median age, where the diagnosis of TSC-associated chordoma is 6.2 months, whereas for chordoma in the general pediatric population it is set to 12 years. The majority of TSC-associated chordomas are localized in skull-based and sacrum regions, and rare in the spine. Chordomas are genetically heterogeneous tumors characterized by chromosomal instability (CIN), and alterations involving PI3K-AKT signaling pathway genes and chromatin remodeling genes. Here we present the 14th case of chordoma associated with TSC in a 1-year-old pediatric patient. Alongside biallelic inactivation of the TSC1 gene, molecular genetic analysis revealed CIN and involvement of epigenetic regulation genes. In addition, we found the engagement of CBX7 and apolipoprotein B editing complex (APOBEC3) genes that were not yet seen in chordomas before. Amplification of CBX7 may epigenetically silence the CDKN2A gene, whereas amplification of APOBEC3 genes can explain the frequent occurrence of CIN in chordomas. We also found that KRAS gene is located in the region with gain status, which may suggest the ineffectiveness of potential EGFR monotherapy. Thus, molecular genetic analysis carried out in this study broadens the horizons of possible approaches for targeted therapies with potential applications for personalized medicine., Competing Interests: The authors declare the following conflict of interests: Maxim Untesco was employed by the company UNIM Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 The Author(s).)

Insulinomatosis is characterized by monohormonality of multiple macro-tumors and micro-tumors that arise synchronously and metachronously in all regions of the pancreas, and often recurring hypoglycemia. One of the main characteristics of insulinomatosis is the presence of insulin-expressing monohormonal endocrine cell clusters that are exclusively composed of proliferating insulin-positive cells, are less than 1 mm in size, and show solid islet-like structure. It is presumed that insulinomatosis affects the entire population of β-cells. With regards to molecular genetics, this phenomenon is not related to mutation in MEN1 gene and is more similar to sporadic benign insulinomas, however, at the moment molecular genetics of this disease remains poorly investigated. NGS sequencing was performed with a panel of 409 cancer-related genes. Results of sequencing were analyzed by bioinformatic algorithms for detecting point mutations and copy number variations. DNA copy number variations were detected that harbor a large number of genes in insulinoma and fewer genes in micro-tumors. qPCR was used to confirm copy number variations at ATRX , FOXL2 , IRS2 and CEBPA genes. Copy number alterations involving FOXL2 , IRS2 , CEBPA and ATRX genes were observed in insulinoma as well as in micro-tumors samples, suggesting that alterations of these genes may promote malignization in the β-cells population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Anoshkin, Vasilyev, Karandasheva, Shugay, Kudryavtseva, Egorov, Gurevich, Mironova, Serikov, Kutsev and Strelnikov.)