Long non-coding RNAs as monitoring tools and therapeutic targets in breast cancer

[Background] Current therapeutic strategies that are used to combat breast cancer vary widely and largely depend on its clinicopathological features, including tumor subtype, size, stage, lymph node involvement, the presence of hormone receptors and/or HER2, as well as the degree of proliferative activity. Recent work has focused on improving our knowledge on the molecular mechanisms that underlie this complex disease. Most of the human genome is transcribed into RNAs that do not encode proteins. These noncoding RNAs may act as mediators in the regulation of gene expression. Based on their size and function, noncoding RNAs are classified into small noncoding RNAs (sncRNAs) and long noncoding RNAs (lncRNAs). LncRNAs have been found to play key roles in relevant biological processes, including breast cancer. As such, lncRNAs have been proposed as diagnostic and prognostic biomarkers, as predictive biomarkers and as putative therapeutic targets.[Conclusions] In this review, we discuss the potential application of lncRNAs for the monitoring and treatment of breast cancer. We conclude that lncRNAs play important roles in the pathophysiology of this disease and may serve as putative therapeutic targets. As such, tumor-specific lncRNAs may be instrumental for improving current breast cancer clinical practices.SMP was supported by the Consejería de Salud y Bienestar Social of Junta de Andalucía through the “‘Nicolás Monardes’” program [C-0040-2016].Peer reviewe

Papel de la proteína de adhesión sináptica neurexina 1 en autismo

1 página. IX Jornadas Andaluzas Salud Investiga. Cádiz 20-22 octubre, 2010.El Trastorno del Espectro Autista (TEA) es un conjunto de síndromes del desarrollo que se caracterizan por déficit en la interacción social, comunicación restringida y comportamientos estereotipados. Hasta un 70% de los casos están asociados a retraso mental. La mayor parte de los casos de TEA se enmarcan dentro de las enfermedades complejas, causadas por la combinación de alelos de susceptibilidad y factores ambientales. Se han identificado mutaciones y variaciones estructurales en genes que codifican proteínas sinápticas, como las neurexinas, que podrían incrementar el riesgo a desarrollar la enfermedad. Los objetivos de nuestro estudio son entender el mecanismo de acción de neurexina-1 beta (NRXN1β) en el desarrollo del TEA.Peer reviewe

Generation of a transgenic mouse model to inhibit the function of beta-neurexin-1, a gene involved in autism spectrum disorders

Póster presentado en la International Meeting for Autism Research, celebrado en San Sebastián en mayo de 2013.[Background] Synapses are established with precision during brain development and are constantly remodeled as a consequence of synaptic activity in the adult networks. Synaptic dysfunction underlies the molecular basis of several neurodevelopmental disorders, such as autism spectrum disorders (ASD). Trans-synaptic adhesion systems can regulate synaptic function, as they organize pre- and postsynaptic protein complexes. One of these adhesion systems is formed by neurexins and neuroligins. These proteins promote the assembly and maturation of synapses through a bidirectional mechanism. In mammals, neurexins are encoded by three genes with two alternative promoters, which produce the long (alpha-neurexins) and the short (beta-neurexins) isoforms. In addition, alternative splicing in the extracellular domain contributes to generate hundreds of neurexins isoforms. Despite the high heterogeneity of the extracellular region, the cytoplasmic domain is common to all neurexin isoforms and it is thought to regulate intracellular signalling. The relevance of neurexins in neurodevelopmental disorders has been highlighted by the identification of mutations in neurexin genes in ASD. Recently, we have suggested a role for synaptic defects of beta-neurexin-1 as a risk factor for autism and mental retardation.[Objectives] To characterize in cultured neurons the effect of a beta-neurexin-1 dominant negative mutant that lacks the cytoplasmic tail (HA-bNrxDC). To inhibit the function of beta-neurexin-1 in vivo by expressing the HA-bNrxDC mutant. To characterize the behavioral phenotype of a double transgenic mice expressing an inducible form of the HA-bNrx1DC mutant (TRE-HA-bNrx1DC/CamKII-tTA).[Methods] In vitro studies have been performed in hippocampal neurons at 10-14 DIV isolated from 18-19 embryonic day rat brains. For in vivo studies we have generated a transgenic mouse line that expresses a HA-tagged beta-neurexin-1 mutant lacking the cytoplasmic domain (HA-bNrx1DC) under the control of the inducible TRE promoter. The TRE-HA-bNrx1DC transgenic mice have been crossed with CAMKII ¿tTA animals to direct the expression of the mutant protein to glutamatergic terminals in vivo.[Results] Our in vitro results suggest that HA-bNrx1DC mutant can function as a dominant negative mutant as it can be recruited to the membrane of glutamatergic synapses through interaction with neuroligin-1, but it inhibits intracellular signalling mediated by the cytoplasmic tail. In vivo we show expression of HA-bNrx1DC in the cortex and hippocampal formation by immunolocalization. Moreover, we have evaluated the behavioral consequences of the lack of beta-neurexin-1 function in TRE-HA-bNrx1DC/CamKII-tTA double transgenic mice.[Conclusions] Inducible expression of a beta-neurexin-1 dominant negative mutant might have implications in the study of autism, as it may help answering to what extent synaptic and behavioral defects due to beta-neurexin-1 dysfunction can be rescued by resuming normal beta-neurexin-1 function.Peer Reviewe

Mutations affecting synaptic levels of neurexin-1ß in autism and mental retardation

The identification of mutations in genes encoding proteins of the synaptic neurexin–neuroligin pathway in different neurodevelopmental disorders, including autism and mental retardation, has suggested the presence of a shared underlying mechanism. A few mutations have been described so far and for most of them the biological consequences are unknown. To further explore the role of the NRXN1β gene in neurodevelopmental disorders, we have sequenced the coding exons of the gene in 86 cases with autism and mental retardation and 200 controls and performed expression analysis of DNA variants identified in patients. We report the identification of four novel independent mutations that affect nearby positions in two regions of the gene/protein: i) sequences important for protein translation initiation, c.− 3G>T within the Kozak sequence, and c.3G>T (p.Met1), at the initiation codon; and ii) the juxtamembrane region of the extracellular domain, p.Arg375Gln and p.Gly378Ser. These mutations cosegregate with different psychiatric disorders other than autism and mental retardation, such as psychosis and attention-deficit/hyperactivity disorder. We provide experimental evidence for the use of an alternative translation initiation codon for c.− 3G>T and p.Met1 mutations and reduced synaptic levels of neurexin-1β protein resulting from p.Met1 and p.Arg375Gln. The data reported here support a role for synaptic defects of neurexin-1β in neurodevelopmental disorders.The authors gratefully thank the participation of patients and their families; Dr. S. Sommer for providing the sequences of PCR primers; Dr. P. Scheiffele for helpful comments; R.J. Meléndez-Cadenas for excellent technical assistance; and Dr. Miguel Lucas for support. This work was funded by grants from the Instituto de Salud Carlos III (ISCIII; PI081446 to F.G.S.) and Junta de Andalucía (P07-CVI-02943 to F.G.S., P07-CVI-0270 to A.M-M. and P06-CVI-02392). R.J.C-G. is a recipient of a fellowship from ISCIII (FI08/00730).Peer Reviewe

Assembling the Dead, Gathering the Living: Radiocarbon Dating and Bayesian Modelling for Copper Age Valencina de la Concepción (Seville, Spain)

The great site of Valencina de la Concepción, near Seville in the lower Guadalquivir valley of southwest Spain, is presented in the context of debate about the nature of Copper Age society in southern Iberia as a whole. Many aspects of the layout, use, character and development of Valencina remain unclear, just as there are major unresolved questions about the kind of society represented there and in southern Iberia, from the late fourth to the late third millennium cal BC. This paper discusses 178 radiocarbon dates, from 17 excavated sectors within the c. 450 ha site, making it the best dated in later Iberian prehistory as a whole. Dates are modelled in a Bayesian statistical framework. The resulting formal date estimates provide the basis for both a new epistemological approach to the site and a much more detailed narrative of its development than previously available. Beginning in the 32nd century cal BC, a long-lasting tradition of simple, mainly collective and often successive burial was established at the site. Mud-vaulted tholoi appear to belong to the 29th or 28th centuries cal BC; large stone-vaulted tholoi such as La Pastora appear to date later in the sequence. There is plenty of evidence for a wide range of other activity, but no clear sign of permanent, large-scale residence or public buildings or spaces. Results in general support a model of increasingly competitive but ultimately unstable social relations, through various phases of emergence, social competition, display and hierarchisation, and eventual decline, over a period of c. 900 years

The maternal genetic make-up of the Iberian Peninsula between the Neolithic and the Early Bronze Age

Abstract Agriculture first reached the Iberian Peninsula around 5700 BCE. However, little is known about the genetic structure and changes of prehistoric populations in different geographic areas of Iberia. In our study, we focus on the maternal genetic makeup of the Neolithic (~ 5500–3000 BCE), Chalcolithic (~ 3000–2200 BCE) and Early Bronze Age (~ 2200–1500 BCE). We report ancient mitochondrial DNA results of 213 individuals (151 HVS-I sequences) from the northeast, central, southeast and southwest regions and thus on the largest archaeogenetic dataset from the Peninsula to date. Similar to other parts of Europe, we observe a discontinuity between hunter-gatherers and the first farmers of the Neolithic. During the subsequent periods, we detect regional continuity of Early Neolithic lineages across Iberia, however the genetic contribution of hunter-gatherers is generally higher than in other parts of Europe and varies regionally. In contrast to ancient DNA findings from Central Europe, we do not observe a major turnover in the mtDNA record of the Iberian Late Chalcolithic and Early Bronze Age, suggesting that the population history of the Iberian Peninsula is distinct in character