Impaired embryonic haematopoiesis yet normal arterial development in the absence of the Notch ligand Jagged1

Specific deletion of Notch1 and RBPjκ in the mouse results in abrogation of definitive haematopoiesis concomitant with the loss of arterial identity at embryonic stage. As prior arterial determination is likely to be required for the generation of embryonic haematopoiesis, it is difficult to establish the specific haematopoietic role of Notch in these mutants. By analysing different Notch-ligand-null embryos, we now show that Jagged1 is not required for the establishment of the arterial fate but it is required for the correct execution of the definitive haematopoietic programme, including expression of GATA2 in the dorsal aorta. Moreover, successful haematopoietic rescue of the Jagged1-null AGM cells was obtained by culturing them with Jagged1-expressing stromal cells or by lentiviral-mediated transduction of the GATA2 gene. Taken together, our results indicate that Jagged1-mediated activation of Notch1 is responsible for regulating GATA2 expression in the AGM, which in turn is essential for definitive haematopoiesis in the mouse

Characterization of new otic enhancers of the pou3f4 gene reveal distinct signaling pathway regulation and spatio-temporal patterns

POU3F4 is a member of the POU-homedomain transcription factor family with a prominent role in inner ear development. Mutations in the human POU3F4 coding unit leads to X-linked deafness type 3 (DFN3), characterized by conductive hearing loss and progressive sensorineural deafness. Microdeletions found 1 Mb 5′ upstream of the coding region also displayed the same phenotype, suggesting that cis-regulatory elements might be present in that region. Indeed, we and others have recently identified several enhancers at the 1 Mb 5′ upstream interval of the pou3f4 locus. Here we characterize the spatio-temporal patterns of these regulatory elements in zebrafish transgenic lines. We show that the most distal enhancer (HCNR 81675) is activated earlier and drives GFP reporter expression initially to a broad ear domain to progressively restrict to the sensory patches. The proximal enhancer (HCNR 82478) is switched later during development and promotes expression, among in other tissues, in sensory patches from its onset. The third enhancer (HCNR 81728) is also active at later stages in the otic mesenchyme and in the otic epithelium. We also characterize the signaling pathways regulating these enhancers. While HCNR 81675 is regulated by very early signals of retinoic acid, HCNR 82478 is regulated by Fgf activity at a later stage and the HCNR 81728 enhancer is under the control of Hh signaling. Finally, we show that Sox2 and Pax2 transcription factors are bound to HCNR 81675 genomic region during otic development and specific mutations to these transcription factor binding sites abrogates HCNR 81675 enhancer activity. Altogether, our results suggest that pou3f4 expression in inner ear might be under the control of distinct regulatory elements that fine-tune the spatio-temporal activity of this gene and provides novel data on the signaling mechanisms controlling pou3f4 function.This work has been supported by grants from MICINN to BA (BFU 2008-00714) and JLG-S (BFU2007-60042/BMC, Petri PET2007_0158, CSD2007-00008), a grant from the Junta de Andalucía to JLG-S (Proyecto de Excelencia CVI-3488) and a Juan de la Cierva postdoctoral fellowship to ARM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscrip

Current state-of-the-art and gaps in platform trials: 10 things you should know, insights from EU-PEARL

Summary: Platform trials bring the promise of making clinical research more efficient and more patient centric. While their use has become more widespread, including their prominent role during the COVID-19 pandemic response, broader adoption of platform trials has been limited by the lack of experience and tools to navigate the critical upfront planning required to launch such collaborative studies. The European Union-Patient-cEntric clinicAl tRial pLatform (EU-PEARL) initiative has produced new methodologies to expand the use of platform trials with an overarching infrastructure and services embedded into Integrated Research Platforms (IRPs), in collaboration with patient representatives and through consultation with U.S. Food and Drug Administration and European Medicines Agency stakeholders. In this narrative review, we discuss the outlook for platform trials in Europe, including challenges related to infrastructure, design, adaptations, data sharing and regulation. Documents derived from the EU-PEARL project, alongside a literature search including PubMed and relevant grey literature (e.g., guidance from regulatory agencies and health technology agencies) were used as sources for a multi-stage collaborative process through which the 10 more important points based on lessons drawn from the EU-PEARL project were developed and summarised as guidance for the setup of platform trials. We conclude that early involvement of critical stakeholder such as regulatory agencies or patients are critical steps in the implementation and later acceptance of platform trials. Addressing these gaps will be critical for attaining the full potential of platform trials for patients. Funding: Innovative Medicines Initiative 2 Joint Undertaking with support from the European Union’s Horizon 2020 research and innovation programme and EFPIA

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.11Nsciescopu

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies