Rabs in Signaling and Embryonic Development.

Rab GTPases play key roles in various cellular processes. They are essential, among other roles, to membrane trafficking and intracellular signaling events. Both trafficking and signaling events are crucial for proper embryonic development. Indeed, embryogenesis is a complex process in which cells respond to various signals and undergo dramatic changes in their shape, position, and function. Over the last few decades, cellular studies have highlighted the novel signaling roles played by Rab GTPases, while numerous studies have shed light on the important requirements of Rab proteins at various steps of embryonic development. In this review, we aimed to generate an overview of Rab contributions during animal embryogenesis. We first briefly summarize the involvement of Rabs in signaling events. We then extensively highlight the contribution of Rabs in shaping metazoan development and conclude with new approaches that will allow investigation of Rab functions in vivo.

RAB21 interacts with TMED10 and modulates its localization and abundance.

Membrane trafficking controls vesicular transport of cargo between cellular compartments. Vesicular trafficking is essential for cellular homeostasis and dysfunctional trafficking is linked to several pathologies such as neurodegenerative diseases. Following endocytosis, early endosomes act as sorting stations of internalized materials, routing cargo toward various fates. One important class of membrane trafficking regulators are RAB GTPases. RAB21 has been associated with multiple functions and regulates integrin internalization, endosomal sorting of specific clathrin-independent cargo and autophagy. Although RAB21 is mostly associated with early endosomes, it has been shown to mediate a specific sorting event at the Golgi. From mass spectrometry data, we identified a GTP-favored interaction between RAB21 and TMED10 and 9, essential regulators of COPI and COPII vesicles. Using RAB21 knockout cells, we describe the role of RAB21 in modulating TMED10 Golgi localization. Taken together, our study suggests a new potential function of RAB21 in modulating TMED10 trafficking, with relevance to neurodegenerative disorders.

APEX2-mediated RAB proximity labeling identifies a role for RAB21 in clathrin-independent cargo sorting.

RAB GTPases are central modulators of membrane trafficking. They are under the dynamic regulation of activating guanine exchange factors (GEFs) and inactivating GTPase-activating proteins (GAPs). Once activated, RABs recruit a large spectrum of effectors to control trafficking functions of eukaryotic cells. Multiple proteomic studies, using pull-down or yeast two-hybrid approaches, have identified a number of RAB interactors. However, due to the in vitro nature of these approaches and inherent limitations of each technique, a comprehensive definition of RAB interactors is still lacking. By comparing quantitative affinity purifications of GFP:RAB21 with APEX2-mediated proximity labeling of RAB4a, RAB5a, RAB7a, and RAB21, we find that APEX2 proximity labeling allows for the comprehensive identification of RAB regulators and interactors. Importantly, through biochemical and genetic approaches, we establish a novel link between RAB21 and the WASH and retromer complexes, with functional consequences on cargo sorting. Hence, APEX2-mediated proximity labeling of RAB neighboring proteins represents a new and efficient tool to define RAB functions.

Recomendaciones sobre aspectos éticos de la investigación cualitativa en la salud / Recommendations on ethical aspects of qualitative research in health

Desde el punto de vista ético, la investigación cualitativa debe cumplir un conjunto de requisitos éticos que son comunes a cualquier tipo de investigación. Además, presenta una serie de problemas peculiares que son abordados en 13 recomendaciones que inciden principalmente en los siguientes puntos: la necesidad de que las relaciones entre el investigador y los sujetos participantes en la investigación se caractericen por la confianza mutua y la integridad profesional; la obligación de informar de las características de la investigación como un proceso abierto que podría hacer necesario solicitar un nuevo consentimiento o revisarlo durante el proceso de investigación; la exigencia de informar y verificar que el participante comprende la diferencia entre investigación y acto terapéutico. Los investigadores han de tener especial cuidado en la publicación de los resultados para mantener la confidencialidad y evitar estigmatización (AU)

From the ethical point of view, qualitative research must meet a set of ethical requirements that are common to any type of research. In addition, it presents a series of unique problems that are addressed in 13 recommendations that impact primarily on the following points: the need for relations between the researcher and the subjects participating in research should be characterized by mutual trust and professional integrity, the obligation to inform of the characteristics of research as an open process that could make it necessary to request a new consent form or review the existing consent form during the investigation process; the requirement to provide information and verify that the participant understands the difference between research and therapeutic act. Researchers should take special care when publishing the results to maintain patient confidentiality and to avoid stigmatization (AU)

[The ethical aspects of population screening programme of rare diseases]. / Recomendaciones sobre los aspectos éticos de los programas de cribado de población para enfermedades raras.

The Committee on Ethics of the Instituto de Investigación de Enfermedades Raras (CEIIER) of the Spanish National Institute of Health Carlos III, presents this article dealing with ethical guidelines regarding the implementation of screening population programmes with special emphasis on genetic screening. After a critical review it has been addressed 24 recommendations concerning 14 topics: evaluation of the opportunity of the programme, including ethical analysis besides scientific evidences and cost/benefits issues; the need to differentiate between research and public health intervention and to built a specific and comprehensive programme; the creation of an interdisciplinary working group which control its implementation and prepare a protocol including justification, development, therapeutic or preventive actions and follow-up activities; the review of the programme by an independent Ethical committee; the guarantee of the voluntary, universal and equitable population access, which requires sufficient information on the programme and their specific relevant facts, as incidental detection of heterozygous state in minors in newborn screening and the relevance of non directive genetic counselling specially in prenatal screening offered to pregnant women; considerations regarding future uses of samples for research purposes; total quality and periodic programme evaluation; guarantee of personal data confidentiality and the conflict of interest statement of the members of all the Committees involved in the programme.

Recomendaciones sobre los aspectos éticos de los programas de cribado de población para enfermedades raras / The ethicals aspects of population screening programme of rare diseases

El Comité de Ética del Instituto de Investigación de EnfermedadesRaras (CEIIER) del Instituto de Salud Carlos III, dentro de lasactividades que desarrolla, ha preparado el presente documento derecomendaciones éticas con respecto a la puesta en marcha de programasde cribado de población, con especial referencia a los cribadosgenéticos. Basándose en una revisión crítica se han elaborado 24recomendaciones concernientes a 14 apartados que inciden principalmenteen los siguientes puntos: la evaluación de la pertinencia delprograma, incorporando al proceso el análisis ético, de las evidenciascientíficas y de la oportunidad de los costes; la necesidad de diferenciarentre investigación e intervención y de que el programa seaespecífico e integral; la creación de un grupo de trabajo interdisciplinarque controle su desarrollo y elabore un protocolo de programaque incluya su justificación, desarrollo y ejecución incluyendo lasactividades terapéuticas o preventivas y actividades de seguimiento;la revisión necesaria del programa por un Comité de Ética independiente;la garantía de acceso voluntario, universal y equitativo querequiere de la información sobre el programa y hechos específicos silos hubiera, como la detección accidental del estado heterocigoto enmenores en los programas de cribado neonatal y las necesidades deconsejo genético; la consideración del uso futuro de las muestrasremanentes; la calidad total y evaluación periódica del programa; lasgarantías de confidencialidad de los datos de carácter personal; ladeclaración de conflictos de intereses de los miembros de losComités implicados en el programa(AU)

The Committee on Ethics of the Instituto de Investigación deEnfermedades Raras (CEIIER) of the Spanish National Institute ofHealth Carlos III, presents this article dealing with ethical guidelinesregarding the implementation of screening population programmeswith special emphasis on genetic screening. After a critical review ithas been addressed 24 recommendations concerning 14 topics: evaluationof the opportunity of the programme, including ethical analysisbesides scientific evidences and cost/benefits issues; the need todifferentiate between research and public health intervention and tobuilt a specific and comprehensive programme; the creation of aninterdisciplinary working group which control its implementationand prepare a protocol including justification, development, therapeuticor preventive actions and follow-up activities; the review of theprogramme by an independent Ethical committee; the guarantee ofthe voluntary, universal and equitable population access, which requiressufficient information on the programme and their specific relevantfacts, as incidental detection of heterozygous state in minors innewborn screening and the relevance of non directive genetic counsellingspecially in prenatal screening offered to pregnant women; considerationsregarding future uses of samples for research purposes;total quality and periodic programme evaluation; guarantee of personaldata confidentiality and the conflict of interest statement of themembers of all the Committees involved in the programme(AU)