Mex3A is an RNA binding protein that can also act as an E3 ubiquitin ligase to control gene expression at the post-transcriptional level. In intestinal adult stem cells, MEX3A is required for cell self-renewal and when overexpressed, MEX3A can contribute to support the proliferation of different cancer cell types. In a completely different context, we found mex3A among the genes expressed in neurogenic niches of the embryonic and adult fish brain and, notably, its expression was downregulated during brain aging. The role of mex3A during embryonic and adult neurogenesis in tetrapods is still unknown. Here, we showed that mex3A is expressed in the proliferative region of the developing brain in both Xenopus and mouse embryos. Using gain and loss of gene function approaches, we showed that, in Xenopus embryos, mex3A is required for neuroblast proliferation and its depletion reduced the neuroblast pool, leading to microcephaly. The tissue-specific overexpression of mex3A in the developing neural plate enhanced the expression of sox2 and msi-1 keeping neuroblasts into a proliferative state. It is now clear that the stemness property of mex3A, already demonstrated in adult intestinal stem cells and cancer cells, is a key feature of mex3a also in developing brain, opening new lines of investigation to better understand its role during brain aging and brain cancer development.

Global population aging is one of the major social and economic challenges of contemporary society. During aging the progressive decline in physiological functions has serious consequences for all organs including brain. The age-related incidence of neurodegenerative diseases coincides with the sharp decline of the amount and functionality of adult neural stem cells. Recently, we identified a short list of brain age-regulated genes by means of next-generation sequencing. Among them znf367 codes for a transcription factor that represents a central node in gene co-regulation networks during aging, but whose function in the central nervous system (CNS), is completely unknown. As proof of concept, we analysed the role of znf367 during Xenopus laevis neurogenesis. By means of a gene loss of function approach limited to the CNS, we suggested that znf367 might act as a key controller of the neuroblast cell cycle, particularly in the progression of mitosis and spindle checkpoint. A candidate gene approach based on a weighted-gene co-expression network analysis, revealed fancd2 and ska3 as possible targets of znf367. The age-related decline of znf367 correlated well with its role during embryonic neurogenesis, opening new lines of investigation also in adult neurogenesis to improved maintenance and even repair of neuronal function.

BackgroundGlioblastoma (GBM) is the most frequent and malignant primary brain tumor in adults and despite the progress in surgical procedures and therapy options, the overall survival remains very poor. Glutamate and α-KG are fundamental elements necessary to support the growth and proliferation of GBM cells. Glutamate oxidative deamination, catalyzed by GLUD2, is the predominant pathway for the production of α-KG.MethodsGLUD2 emerged from the RNA-seq analysis of 13 GBM patients, performed in our laboratory and a microarray analysis of 77 high-grade gliomas available on the Geo database. Thereafter, we investigated GLUD2 relevance in cancer cell behavior by GLUD2 overexpression and silencing in two different human GBM cell lines. Finally, we overexpressed GLUD2 in-vivo by using zebrafish embryos and monitored the developing central nervous system.FindingsGLUD2 expression was found associated to the histopathological classification, prognosis and survival of GBM patients. Moreover, through in-vitro functional studies, we showed that differences in GLUD2 expression level affected cell proliferation, migration, invasion, colony formation abilities, cell cycle phases, mitochondrial function and ROS production. In support of these findings, we also demonstrated, with in-vivo studies, that GLUD2 overexpression affects glial cell proliferation without affecting neuronal development in zebrafish embryos.InterpretationWe concluded that GLUD2 overexpression inhibited GBM cell growth suggesting a novel potential drug target for control of GBM progression. The possibility to enhance GLUD2 activity in GBM could result in a blocked/reduced proliferation of GBM cells without affecting the survival of the surrounding neurons.

Platelet-derived growth factor B (PDGF-B) belongs to the mitogen and growth factor family and like the other members it has many roles in cell differentiation, proliferation and migration during development, adult life and in pathological conditions. Among them it has been observed that aberrant PDGF signalling is frequently linked to glioma development and progression, and Pdgf-b over-expression in mouse neural progenitors leads to the formation of gliomas. Despite this evidence, the mechanisms underlying PDGF-B driven tumorigenesis and its role during brain development are not fully understood. In order to contribute to clarifying possible new roles of pdgf-b signalling, we present here the embryonic gene expression pattern of pdgf-b, so far unknown in early vertebrate development. By using Xenopus laevis as a model system we performed qRT-PCR and whole mount in situ hybridization. Pdgf-b mRNA is expressed in discrete regions of the developing central nervous system, in the cranial nerve placodes and in the notochord. We also compared the gene expression of pdgf-b with that of its receptor pdgfr-a suggesting so far unsuspected roles for this signalling pathway during the development of specific embryonic structures. KEY WORDS: PDGF-B, PDGF receptor a, central nervous system, neural crest, Xenopus laevisPlatelet-derived growth factor (PDGF) family comprises two tyrosine kinase receptors (PDGFR-a and -b) and four ligands (PDGF-A, -B, -C, and -D) that form homodimers or the heterodimer AB (Demoulin and Essaghir, 2014). The active ligand-receptor complex consists of two receptor chains associated with one dimeric ligand. While PDGFR-a binds to all PDGF isoforms except for PDGF-DD, PDGFR-b binds only to PDGF-BB and -DD (Fig.1). Also a heterodimeric ab receptor has been reported that binds to PDGF-AB, -BB and possibly -CC and -DD (Demoulin and Essaghir, 2014). The members of this family have been extensively studied for more than 30 years in development, adult homeostasis and disease (Heldin, 2013, Heldin, 2014, Hoch and Soriano, 2003. Pdgf-a expression was recently characterized in mouse tissues and in early embryonic development, showing its involvement in developmental processes including gastrulation and craniofacial development (Andrae et al., 2014, Eberhart et al., 2008. On the contrary, for pdgf-b the only information available mainly concern its role during embryonic angiogenesis (Hoch and Soriano, 2003, Leveen et al., 1994), and a complete gene expression pattern in vertebrate embryogenesis is still lacking. Functional studies using a knock out mouse for pdgf-b showed abnormal kidney glomeruli, heart and blood vessel dilation, anemia, thrombocytopenia, haemorrhages and perinatal death (Betsholtz, 1995, Leveen et al., 1994. However, in this mutant line, BB homodimer and AB heterodimer were simultaneously abrogated, making difficult to precisely define the specific role of pdgf-b alone during embryogenesis. Furthermore, due to extensive perinatal haemorrhages, other possible phenotypes caused by the...