Retinoic Acid Induced 1, RAI1: A Dosage Sensitive Gene Related to Neurobehavioral Alterations Including Autistic Behavior

Genomic structural changes, such as gene Copy Number Variations (CNVs) are extremely abundant in the human genome. An enormous effort is currently ongoing to recognize and catalogue human CNVs and their associations with abnormal phenotypic outcomes. Recently, several reports related neuropsychiatric diseases (i.e. autism spectrum disorders, schizophrenia, mental retardation, behavioral problems, epilepsy) with specific CNV. Moreover, for some conditions, both the deletion and duplication of the same genomic segment are related to the phenotype. Syndromes associated with CNVs (microdeletion and microduplication) have long been known to display specific neurobehavioral traits. It is important to note that not every gene is susceptible to gene dosage changes and there are only a few dosage sensitive genes. Smith-Magenis (SMS) and Potocki-Lupski (PTLS) syndromes are associated with a reciprocal microdeletion and microduplication within chromosome 17p11.2. in humans. The dosage sensitive gene responsible for most phenotypes in SMS has been identified: the Retinoic Acid Induced 1 (RAI1). Studies on mouse models and humans suggest that RAI1 is likely the dosage sensitive gene responsible for clinical features in PTLS. In addition, the human RAI1 gene has been implicated in several neurobehavioral traits as spinocerebellar ataxia (SCA2), schizophrenia and non syndromic autism. In this review we discuss the evidence of RAI1 as a dosage sensitive gene, its relationship with different neurobehavioral traits, gene structure and mutations, and what is known about its molecular and cellular function, as a first step in the elucidation of the mechanisms that relate dosage sensitive genes with abnormal neurobehavioral outcomes

The molecular role of GTF2IRD1: a protein involved in the neurodevelopmental abnormalities of Williams-Beuren syndrome

Background: GTF2IRD1 is a member of the GTF2I gene family, located on chromosome 7 in a region prone to duplications and deletions in humans. Hemizygous deletions cause Williams-Beuren syndrome (WBS) and duplications cause WBS duplication syndrome. Human mapping data and analyses of mouse knockouts implicate GTF2IRD1 as the prime candidate for the craniofacial abnormalities, mental retardation, visuospatial construction deficits and hypersociability of WBS. Aims: The aim of this work was to study the cellular and molecular role of GTF2IRD1 by investigating: i) the cellular localisation of GTF2IRD1; ii) its protein interacting partners; iii) the gene dysregulation caused by GTF2IRD1 loss; and iv) the presence of GTF2IRD1 in epigenetic complexes regulating gene expression. Results: i) Immunofluorescence analyses in mammalian cell lines and in human ES cell-derived neurons showed endogenous GTF2IRD1 as a nuclear speckle protein. The comparison of this punctate pattern with markers of nuclear sub-compartments and chromatin marks supports an association with developmentally regulated silent chromatin. ii) To define functional relationships, yeast two-hybrid screenings were used to isolate novel interaction partners. Most of the nuclear-localised interactions were validated in mammalian cells, being predominantly proteins involved in chromatin modification and transcriptional regulation. The sites of interaction in GTF2IRD1 were mapped to specific domains. iii) To identify transcriptional changes arising from GTF2IRD1 loss, microarray studies were conducted in siRNA-treated HeLa cells and brain tissue from Gtf2ird1 knockout mice. In the corpus striatum, qPCR validation indicated up-regulation of genes involved in neuronal development and immediate-early response genes that may explain some of the observed neurobehavioural phenotypes. iv) GTF2IRD1 was found to be involved in chromatin modifying complexes by direct associations with histone deacetylases and can affect their enzymatic activity. Conclusions: The results of this thesis indicate that GTF2IRD1 forms complexes with DNA-binding and chromatin modifying proteins to regulate gene expression through epigenetic mechanisms that are controlled in a tissue specific manner. The sites of protein interactions indicate key features regarding the evolution of GTF2IRD1 and integration with tight post-translational regulation, fitting well with the concept of human disease states caused by copy number variation

Mitigating losses: how scientific organisations can help address the impact of the COVID-19 pandemic on early-career researchers.

Scientific collaborations among nations to address common problems and to build international partnerships as part of science diplomacy is a well-established notion. The international flow of people and ideas has played an important role in the advancement of the 'Sciences' and the current pandemic scenario has drawn attention towards the genuine need for a stronger role of science diplomacy, science advice and science communication. In dealing with the COVID-19 pandemic, visible interactions across science, policy, science communication to the public and diplomacy worldwide have promptly emerged. These interactions have benefited primarily the disciplines of knowledge that are directly informing the pandemic response, while other scientific fields have been relegated. The effects of the COVID-19 pandemic on scientists of all disciplines and from all world regions are discussed here, with a focus on early-career researchers (ECRs), as a vulnerable population in the research system. Young academies and ECR-driven organisations could suggest ECR-powered solutions and actions that could have the potential to mitigate these effects on ECRs working on disciplines not related to the pandemic response. In relation with governments and other scientific organisations, they can have an impact on strengthening and creating fairer scientific systems for ECRs at the national, regional, and global level

Podocyte-Specific Overexpression of Wild Type or Mutant Trpc6 in Mice Is Sufficient to Cause Glomerular Disease

Mutations in the TRPC6 calcium channel (Transient receptor potential channel 6) gene have been associated with familiar forms of Focal and Segmental Glomerulosclerosis (FSGS) affecting children and adults. In addition, acquired glomerular diseases are associated with increased expression levels of TRPC6. However, the exact role of TRPC6 in the pathogenesis of FSGS remains to be elucidated. In this work we describe the generation and phenotypic characterization of three different transgenic mouse lines with podocyte-specific overexpression of the wild type or any of two mutant forms of Trpc6 (P111Q and E896K) previously related to FSGS. Consistent with the human phenotype a non-nephrotic range of albuminuria was detectable in almost all transgenic lines. The histological analysis demonstrated that the transgenic mice developed a kidney disease similar to human FSGS. Differences of 2–3 folds in the presence of glomerular lesions were found between the non transgenic and transgenic mice expressing Trpc6 in its wild type or mutant forms specifically in podocytes. Electron microscopy of glomerulus from transgenic mice showed extensive podocyte foot process effacement. We conclude that overexpression of Trpc6 (wild type or mutated) in podocytes is sufficient to cause a kidney disease consistent with FSGS. Our results contribute to reinforce the central role of podocytes in the etiology of FSGS. These mice constitute an important new model in which to study future therapies and outcomes of this complex disease

Mitigating losses: how scientific organisations can help address the impact of the COVID-19 pandemic on early-career researchers

Scientific collaborations among nations to address common problems and to build international partnerships as part of science diplomacy is a well-established notion. The international flow of people and ideas has played an important role in the advancement of the ‘Sciences’ and the current pandemic scenario has drawn attention towards the genuine need for a stronger role of science diplomacy, science advice and science communication. In dealing with the COVID-19 pandemic, visible interactions across science, policy, science communication to the public and diplomacy worldwide have promptly emerged. These interactions have benefited primarily the disciplines of knowledge that are directly informing the pandemic response, while other scientific fields have been relegated. The effects of the COVID-19 pandemic on scientists of all disciplines and from all world regions are discussed here, with a focus on early-career researchers (ECRs), as a vulnerable population in the research system. Young academies and ECR-driven organisations could suggest ECR-powered solutions and actions that could have the potential to mitigate these effects on ECRs working on disciplines not related to the pandemic response. In relation with governments and other scientific organisations, they can have an impact on strengthening and creating fairer scientific systems for ECRs at the national, regional, and global level