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The adult mammalian brain retains some capacity to replenish neurons and glia, holding promise for brain regeneration. Thus, understanding the mechanisms controlling adult neural stem cell (NSC) differentiation is crucial. Paradoxically, adult NSCs in the subependymal zone transcribe genes associated with both multipotency maintenance and neural differentiation, but the mechanism that prevents conflicts in fate decisions due to these opposing transcriptional programmes is unknown. Here we describe intron detention as such control mechanism. In NSCs, while multiple mRNAs from stemness genes are spliced and exported to the cytoplasm, transcripts from differentiation genes remain unspliced and detained in the nucleus, and the opposite is true under neural differentiation conditions. We also show that m6A methylation is the mechanism that releases intron detention and triggers nuclear export, enabling rapid and synchronized responses. m6A RNA methylation operates as an on/off switch for transcripts with antagonistic functions, tightly controlling the timing of NSCs commitment to differentiation.

Melanoma is an aggressive form of skin cancer due to its high metastatic abilities and resistance to therapies. Melanoma cells reside in a heterogeneous tumour microenvironment that acts as a crucial regulator of its progression. Snail1 is an epithelial-to-mesenchymal transition transcription factor expressed during development and reactivated in pathological situations including fibrosis and cancer. In this work, we show that Snail1 is activated in the melanoma microenvironment, particularly in fibroblasts. Analysis of mouse models that allow stromal Snail1 depletion and therapeutic Snail1 blockade indicate that targeting Snail1 in the tumour microenvironment decreases melanoma growth and lung metastatic burden, extending mice survival. Transcriptomic analysis of melanoma-associated fibroblasts and analysis of the tumours indicate that stromal Snail1 induces melanoma growth by promoting an immunosuppressive microenvironment and a decrease in anti-tumour immunity. This study unveils a novel role of Snail1 in melanoma biology and supports its potential as a therapeutic target.

Eph receptor (Eph) and ephrin signaling regulate fundamental developmental processes through both forward and reverse signaling triggered upon cell–cell contact. In vertebrates, they are both classified into classes A and B, and some representatives have been identified in many metazoan groups, where their expression and functions have been well studied. We have extended previous phylogenetic analyses and examined the presence of Eph and ephrins in the tree of life to determine their origin and evolution. We have found that 1) premetazoan choanoflagellates may already have rudimental Eph/ephrin signaling as they have an Eph-/ephrin-like pair and homologs of downstream-signaling genes; 2) both forward- and reverse-downstream signaling might already occur in Porifera since sponges have most genes involved in these types of signaling; 3) the nonvertebrate metazoan Eph is a type-B receptor that can bind ephrins regardless of their membrane-anchoring structure, glycosylphosphatidylinositol, or transmembrane; 4) Eph/ephrin cross-class binding is specific to Gnathostomata; and 5) kinase-dead Eph receptors can be traced back to Gnathostomata. We conclude that Eph/ephrin signaling is of older origin than previously believed. We also examined the presence of protein domains associated with functional characteristics and the appearance and conservation of downstream-signaling pathways to understand the original and derived functions of Ephs and ephrins. We find that the evolutionary history of these gene families points to an ancestral function in cell–cell interactions that could contribute to the emergence of multicellularity and, in particular, to the required segregation of cell populations.

Melanoma is the most aggressive form of skin cancer. Together with the recent advances in immunotherapy, targeted therapy with inhibitors of the Mitogen Activated Protein Kinase (MAPKi) pathway including BRAF and MEK inhibitors has greatly improved the clinical outcome of these patients. Unfortunately, due to genetic and non-genetic events, many patients develop resistance to MAPKi. Melanoma phenotypic plasticity, understood as the ability of melanoma cells to dynamically transition between different states with varying levels of differentiation/dedifferentiation, is key for melanoma progression. Lineage plasticity has also emerged as an important mechanism of non-genetic adaptive melanoma drug resistance in the clinic (Arozarena & Wellbrock, 2019), highlighting the need for a deeper characterization of the mechanisms that control this process. In this issue of EMBO Molecular Medicine, Diazzi et al (2022) identify a mechanism regulating MAPKi-induced phenotypic plasticity and resistance, providing evidence to support the use of an anti-fibrotic drug as a potential novel combinatorial therapeutic approach.

[Introduction]: Melanoma is a very aggressive skin cancer, known for its high degree of plasticity and heterogeneity that confers high metastatic capabilities and resistance to therapies. Increasing evidences indicate that melanoma progression is not only regulated by mutationdriven mechanisms but also by non-genetic mechanisms that play an important role in melanoma phenotypic plasticity. The reactivation of the expression of neural crest genes in melanoma is associated to progression and resistance to therapies. Among those, epithelialto-mesenchymal transcription factors (EMT-TFs) have been proposed to regulate reversible switches between phenotypic states driving melanoma progression. However the role of Prrx1, an important EMT inducer also expressed during neural crest development, has not been investigated in detail., [Material and Methods]: We have generated a clinically relevant melanoma mouse model that cannot reactivate Prrx1 expression in melanocytes to address the contribution of this EMT-TF to melanoma initiation, progression and responses to therapies., [Results and Discussions]: We have found that Prrx1 is expressed in melanoma and that Prrx1 down-regulation induces cell cycle retention and reduces cell proliferation and cancer stem-like properties in melanoma cells., [Conclusion]: We have detected an effect of Prrx1 on proliferation in melanoma cell lines and their stem cell abilities, but we are still characterizing the effect of this transcription factor in vivo to melanoma initiation, progression and responses to therapies.

Ángela Nieto, del Instituto de Neurociencias de Alicante, ha recibido el máximo reconocimiento del programa, que elige a una eminencia científica femenina en cada uno de los cinco continentes. Por su parte, Cristina Romera Castillo, investigadora del Instituto de Ciencias del Mar, ha sido premiada en la categoría de Talento Emergente. Las instituciones en las que trabajan ambas son del CSIC

CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research.

When referring to the epithelial-to-mesenchymal transition (EMT), readers are familiar with sentences alluding to its pivotal role both in embryonic development and in disease. Following that argument, usually there is a point on the importance of studying the process and the impact it has on the design of therapeutic strategies. However, it is also very common to find arguments on how the EMT is very difficult to tackle, being a somehow obscure and complex process, where the field cannot reach universal conclusions, particularly in pathological contexts. Even worse, it is sometimes defined as a process that cannot be described with universal markers, making it therefore very difficult for cancer studies, where there is a need to use optimal animal models and stratify patients for differential therapeutic strategies. In the face of all this, the question is whether you have been frightened off working on pathological EMTs, or even if you are not interested anymore and would prefer waiting till the field reaches a steady state of robust knowledge. Do not be afraid and be interested now. It only involves being more plastic, like the EMT itself.

La transición epitelio mesénquima (EMT) confiere propiedades migratorias e invasivas a las células, y es crucial para la formación de muchos tejidos y órganos durante el desarrollo embrionario. Este programa celular se acciona por la activación de factores de transcripción (EMT-TFs) que pertenecen a distintas familias de genes, incluyendo Snail, Twist y Prrx. Durante el desarrollo embrionario, se expresan en áreas de EMT que producen diferentes derivados del mesodermo y su estudio a lo largo de los años ha mostrado que son importantes para el desarrollo de las extremidades y del esqueleto craneofacial. Los EMT-TFs se expresan en territorios distintos o solapantes, llevando a cabo funciones específicas o cooperativas. En el adulto, la reactivación de la EMT contribuye a la progresión de enfermedades como la fibrosis y el cáncer. El gen Prrx1, que se fue identificado como EMTTF en nuestro laboratorio, produce tres isoformas por procesamiento alternativo de los transcritos, cuya función no está bien caracterizada. Snail1 es un EMT-TF clásico, que está muy alto en la jerarquía temporal de la EMT durante el desarrollo embrionario y durante la progresión del cáncer, y su expresión siempre precede a la de Prrx1. Por otro lado, Twist1 es otro EMT-TF clásico cuyo patrón de expresión es muy similar al de Prrx1 en desarrollo embrionario y cáncer. Hemos generado y caracterizado diferentes líneas de ratones transgénicos que nos han permitido estudiar la función de estos EMT-TFs, incluyendo las isoformas de Prrx1, y sus interacciones génicas durante el desarrollo embrionario de ratón. Hemos descubierto interacciones entre Prrx1 y Snail1 en la formación de los derivados craneofaciales y entre Prrx1 y Twist1 en la morfogénesis de los dedos. Además, hemos observado que Prrx1 se expresa específicamente en las células murales durante el desarrollo embrionario y en ratones adultos y hemos observado que Prrx1 es necesario para la integridad de la vasculatura de la retina y de los pulmon

[EN] The life-long persistence of adult neural stem cells (NSCs) requires the accurate balance between their self-renewal, proliferation and differentiation. Recent studies analyzing the transcriptomic dynamics that take place during adult neurogenesis have reveal that post-transcriptional regulation may have a more relevant role than anticipated in the control of NSC biology and function. In this thesis, we have uncovered a novel regulatory mechanism that refines the control of Scratch1 expression during adult neurogenesis. We have shown that this gene is expressed in the adult subependymal zone (SEZ), both in NSCs, transient amplifying progenitors (TAPs) and neuroblasts, exhibiting increasing levels as NSCs progress into the lineage; and fulfilling several functions during the process of differentiation. On the one hand, this transcription factor acts downstream of p53, repressing the transcription of it targets Bbc3 (Puma) and Cdkn1a (p21), which in turn protects the differentiating cells form undergoing apoptosis and, at the same time, stimulates their proliferation. On the other hand, Scratch1 promotes neuronal differentiation, favoring neurogenesis at the expense of gliogenesis. Additionally, we have also determined that Scracth1 starts to be expressed when stem cells acquire the neural identity, but its transcripts are retained in the nucleus of NSCs due to intron detention. This event of regulated splicing is possible thanks to the progressive enlargement of the polypyrimidine tract of its only intron during the evolution of vertebrates, leading to the generation of a suboptimal splice site in mammals. By contrast, in response to the neural differentiation signal, Scratch1 mRNA is m6A modified and consequently spliced and exported to the cytoplasm, where it can be translated. Finally, we have shown that intron detention in this context is not specific for Scratch1 mRNA, but rather it also controls the translational availability of multiple transcripts associ, [ES] El mantenimiento de la población de células madres neurales (NSCs) durante toda la vida del individuo requiere un balance preciso entre su auto-renovación, proliferación y diferenciación. Estudios recientes en los que se han analizado los cambios transcripcionales que tienen lugar durante la neurogénesis adulta han revelado que la regulación post-transcripcional podría tener un peso mayor en el control de la biología y la función de las NSCs de lo que se pensaba previamente. En esta tesis, hemos identificado un nuevo mecanismo de regulación de la expresión del factor de transcripción Scratch1 durante la neurogénesis adulta. Hemos mostrado que este gen se expresa en la zona subependimaria (SEZ) adulta, tanto en NSCs como en progenitores (TAPs) y neuroblastos, presentando niveles crecientes de expresión a medida que las NSCs progresan en el linaje. Además, Scratch1 lleva a cabo diversas funciones durante el proceso de diferenciación. Por una parte, actúa por debajo de p53, reprimiendo la transcripción de sus dianas Bbc3 (Puma) y Cdkn1a (p21), y protegiendo a las células en diferenciación de sufrir apoptosis a la vez que estimula su proliferación. Por otra parte, Scratch1 promueve la diferenciación neuronal, favoreciendo la neurogénesis a expensas de la gliogénesis. Además, hemos determinado que Scratch1 empieza expresarse cuando las células madre adquieren la identidad neural, aunque sus tránscritos permanecen dentro del núcleo de las NSCs debido a un procesamiento deficiente del único intrón en su mRNA. Este evento de splicing regulado es posible gracias a la expansión progresiva de la serie de polipirimidinas (PPT) durante la evolución de los vertebrados, dando lugar a la generación de un sitio de splicing subóptimo en mamíferos. En respuesta a la señal de diferenciación, se induce la metilación (m6A) del mRNA y los tránscritos son procesados y exportados al citoplasma, donde pueden ser traducidos. Por último, hemos encontrado que la detención de intrones no so

The pronephros is the first renal structure in the embryo, arising after mesenchymal to epithelial transition (MET) of the intermediate mesoderm, where Pax2 induces epithelialisation of the mesenchyme. Here we show that, in the early embryo, Snail1 directly represses Pax2 transcription maintaining the intermediate mesoderm in an undifferentiated state. Reciprocally, Pax2 directly represses Snail1 expression to induce MET upon receiving differentiation signals. We also show that BMP7 acts as one such signal by downregulating Snail1 and upregulating Pax2 expression. This, together with the Snail1/Pax2 reciprocal repression, establishes a regulatory loop in a defined region along the anteroposterior axis, the bistability domain within the transition zone, where differentiation of the neural tube and the somites are known to occur. Thus, we show that the antagonism between Snail1 and Pax2 determines the epithelial/mesenchymal state during the differentiation of the intermediate mesoderm and propose that the bistability zone extends to the intermediate mesoderm, synchronizing the differentiation of tissues aligned along the mediolateral embryonic axis.

Substance use disorders are a group of diseases that are associated with social, professional, and family impairment and that represent a high socio-economic impact on the health systems of countries around the world. These disorders present a very complex diagnosis and treatment regimen due to the lack of suitable biomarkers supporting the correct diagnosis and classification and the difficulty of selecting effective therapies. Over the last few years, several studies have pointed out that these addictive disorders are associated with systemic and central nervous system inflammation, which could play a relevant role in the onset and progression of these diseases. Therefore, identifying different immune system components as biomarkers of such addictive disorders could be a crucial step to promote appropriate diagnosis and treatment. Thus, this work aims to provide an overview of the immune system alterations that may be biomarkers of various addictive disorders.

El Consejo Europeo de Investigación (ERC, por sus siglas en inglés) cumplió 10 años el 24 de marzo de 2017. A lo largo de esta década de vida, se ha financiado a unos 7.000 investigadores, permitiendo la publicación de cerca de 100.000 artículos en revistas científicas internacionales. En España, cerca de 400 investigadores han recibido un total de 650 millones de euros y el Consejo Superior de Investigaciones Científicas (CSIC) destaca por ser la institución española con mayor número de ayudas, por delante de la Universidad Pompeu Fabra, el Instituto de Ciencias Fotónicas, la Universidad de Barcelona y el Centro de Regulación Genómica. Entre los más de 400 proyectos que han obtenido una ayuda del Consejo Europeo de Investigación en España, más de un centenar han recaído en el CSIC.