Compound screening in biological assays and subsequent optimization of hits is indispensable for the development of new molecular research tools and drug candidates. To facilitate such discoveries, the European Research Infrastructure EU-OPENSCREEN was founded recently with the support of its member countries and the European Commission. Its distributed character harnesses complementary knowledge, expertise, and instrumentation in the discipline of chemical biology from 20 European partners, and its open working model ensures that academia and industry can readily access EU-OPENSCREEN's compound collection, equipment, and generated data. To demonstrate the power of this collaborative approach, this perspective article highlights recent projects from EU-OPENSCREEN partner institutions. These studies yielded (1) 2-aminoquinazolin-4(3 H)-ones as potential lead structures for new antimalarial drugs, (2) a novel lipodepsipeptide specifically inducing apoptosis in cells deficient for the pVHL tumor suppressor, (3) small-molecule-based ROCK inhibitors that induce definitive endoderm formation and can potentially be used for regenerative medicine, (4) potential pharmacological chaperones for inborn errors of metabolism and a familiar form of acute myeloid leukemia (AML), and (5) novel tankyrase inhibitors that entered a lead-to-candidate program. Collectively, these findings highlight the benefits of small-molecule screening, the plethora of assay designs, and the close connection between screening and medicinal chemistry within EU-OPENSCREEN.

• MeSH
• kooperační chování * MeSH
• lidé MeSH
• objevování léků metody   MeSH
• preklinické hodnocení léčiv MeSH
• rychlé screeningové testy MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH

BACKGROUND: TALE-class homeodomain transcription factors Meis and Pbx play important roles in formation of the embryonic brain, eye, heart, cartilage or hematopoiesis. Loss-of-function studies of Pbx1, 2 and 3 and Meis1 documented specific functions in embryogenesis, however, functional studies of Meis2 in mouse are still missing. We have generated a conditional allele of Meis2 in mice and shown that systemic inactivation of the Meis2 gene results in lethality by the embryonic day 14 that is accompanied with hemorrhaging. RESULTS: We show that neural crest cells express Meis2 and Meis2-defficient embryos display defects in tissues that are derived from the neural crest, such as an abnormal heart outflow tract with the persistent truncus arteriosus and abnormal cranial nerves. The importance of Meis2 for neural crest cells is further confirmed by means of conditional inactivation of Meis2 using crest-specific AP2α-IRES-Cre mouse. Conditional mutants display perturbed development of the craniofacial skeleton with severe anomalies in cranial bones and cartilages, heart and cranial nerve abnormalities. CONCLUSIONS: Meis2-null mice are embryonic lethal. Our results reveal a critical role of Meis2 during cranial and cardiac neural crest cells development in mouse.

• MeSH
• chrupavka abnormality   embryologie   MeSH
• crista neuralis embryologie   metabolismus   MeSH
• forkhead transkripční faktory biosyntéza   genetika   MeSH
• hlavové nervy embryologie   MeSH
• homeodoménové proteiny genetika   MeSH
• krvácení genetika   MeSH
• lebka embryologie   inervace   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• represorové proteiny biosyntéza   genetika   MeSH
• srdce embryologie   MeSH
• transkripční faktor SOX9 biosyntéza   genetika   MeSH
• vrozené srdeční vady embryologie   genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Wnt/beta-catenin signaling regulates many processes during vertebrate development. To study transcriptional targets of canonical Wnt signaling, we used the conditional Cre/loxP system in mouse to ectopically activate beta-catenin during central nervous system development. We show that the activation of Wnt/beta-catenin signaling in the embryonic mouse telencephalon results in the up-regulation of Sp5 gene, which encodes a member of the Sp1 transcription factor family. A proximal promoter of Sp5 gene is highly evolutionarily conserved and contains five TCF/LEF binding sites that mediate direct regulation of Sp5 expression by canonical Wnt signaling. We provide evidence that Sp5 works as a transcriptional repressor and has three independent repressor domains, called R1, R2, and R3, respectively. Furthermore, we show that the repression activity of R1 domain is mediated through direct interaction with a transcriptional corepressor mSin3a. Finally, our data strongly suggest that Sp5 has the same DNA binding specificity as Sp1 and represses Sp1 target genes such as p21. We conclude that Sp5 transcription factor mediates the downstream responses to Wnt/beta-catenin signaling by directly repressing Sp1 target genes.

• MeSH
• beta-katenin metabolismus   MeSH
• buněčné linie MeSH
• down regulace fyziologie   MeSH
• financování organizované MeSH
• genetická transkripce fyziologie   MeSH
• konzervovaná sekvence MeSH
• lidé MeSH
• molekulární sekvence - údaje MeSH
• myši inbrední C57BL MeSH
• myši transgenní MeSH
• myši MeSH
• promotorové oblasti (genetika) fyziologie   MeSH
• proteiny Wnt metabolismus   MeSH
• reportérové geny MeSH
• represorové proteiny metabolismus   MeSH
• sekvence aminokyselin MeSH
• signální transdukce fyziologie   MeSH
• terciární struktura proteinů MeSH
• transkripční faktor Sp1 metabolismus   MeSH
• transkripční faktory genetika   chemie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH

beta-Catenin plays a key role in cadherin-mediated cell adhesion as well as in canonical Wnt signaling. To study the role of beta-catenin during eye development, we used conditional Cre/loxP system in mouse to inactivate beta-catenin in developing lens and retina. Inactivation of beta-catenin does not suppress lens fate, but instead results in abnormal morphogenesis of the lens. Using BAT-gal reporter mice, we show that beta-catenin-mediated Wnt signaling is notably absent from lens and neuroretina throughout eye development. The observed defect is therefore likely due to the cytoskeletal role of beta-catenin, and is accompanied by impaired epithelial cell adhesion. In contrast, inactivation of beta-catenin in the nasal ectoderm, an area with active Wnt signaling, results in formation of crystallin-positive ectopic lentoid bodies. These data suggest that, outside of the normal lens, beta-catenin functions as a coactivator of canonical Wnt signaling to suppress lens fate

• MeSH
• beta-katenin fyziologie   genetika   MeSH
• buněčná adheze MeSH
• choristom genetika   vrozené   MeSH
• financování organizované MeSH
• morfogeneze genetika   MeSH
• myši transgenní MeSH
• myši MeSH
• nemoci nosu genetika   vrozené   MeSH
• oči embryologie   MeSH
• oční čočka cytologie   embryologie   MeSH
• proteiny Wnt fyziologie   MeSH
• signální transdukce genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH