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- Castelo-Branco, GA, et al.
(författare)
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Differential regulation of midbrain dopaminergic neuron development by Wnt-1, Wnt-3a, and Wnt-5a
- 2003
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 100:22, s. 12747-12752
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Tidskriftsartikel (refereegranskat)abstract
- The Wnts are a family of glycoproteins that regulate cell proliferation, fate decisions, and differentiation. In our study, we examined the contribution of Wnts to the development of ventral midbrain (VM) dopaminergic (DA) neurons. Our results show that β-catenin is expressed in DA precursor cells and that β-catenin signaling takes place in these cells, as assessed in TOPGAL [Tcf optimal-promoter β-galactosidase] reporter mice. We also found that Wnt-1, -3a, and -5a expression is differentially regulated during development and that partially purified Wnts distinctively regulate VM development. Wnt-3a promoted the proliferation of precursor cells expressing the orphan nuclear receptor-related factor 1 (Nurr1) but did not increase the number of tyrosine hydroxylase-positive neurons. Instead, Wnt-1 and -5a increased the number of rat midbrain DA neurons in rat embryonic day 14.5 precursor cultures by two distinct mechanisms. Wnt-1 predominantly increased the proliferation of Nurr1+ precursors, up-regulated cyclins D1 and D3, and down-regulated p27 and p57 mRNAs. In contrast, Wnt-5a primarily increased the proportion of Nurr1+ precursors that acquired a neuronal DA phenotype and up-regulated the expression of Ptx3 and c-ret mRNA. Moreover, the soluble cysteine-rich domain of Frizzled-8 (a Wnt inhibitor) blocked endogenous Wnts and the effects of Wnt-1 and -5a on proliferation and the acquisition of a DA phenotype in precursor cultures. These findings indicate that Wnts are key regulators of proliferation and differentiation of DA precursors during VM neurogenesis and that different Wnts have specific and unique activity profiles.
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| 4. |
- Becker, M, et al.
(författare)
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Presynaptic dysfunction in CASK-related neurodevelopmental disorders
- 2020
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 10:1, s. 312-
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Tidskriftsartikel (refereegranskat)abstract
- CASK-related disorders are genetically defined neurodevelopmental syndromes. There is limited information about the effects of CASK mutations in human neurons. Therefore, we sought to delineate CASK-mutation consequences and neuronal effects using induced pluripotent stem cell-derived neurons from two mutation carriers. One male case with autism spectrum disorder carried a novel splice-site mutation and a female case with intellectual disability carried an intragenic tandem duplication. We show reduction of CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of genes involved in presynaptic development and of CASK protein interactors. Furthermore, CASK-deficient neurons showed decreased inhibitory presynapse size as indicated by VGAT staining, which may alter the excitatory–inhibitory (E/I) balance in developing neural circuitries. Using in vivo magnetic resonance spectroscopy quantification of GABA in the male mutation carrier, we further highlight the possibility to validate in vitro cellular data in the brain. Our data show that future pharmacological and clinical studies on targeting presynapses and E/I imbalance could lead to specific treatments for CASK-related disorders.
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| 8. |
- Shen, J. X., et al.
(författare)
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Organotypic and Microphysiological Models of Liver, Gut, and Kidney for Studies of Drug Metabolism, Pharmacokinetics, and Toxicity
- 2020
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Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 33:1, s. 38-60
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Tidskriftsartikel (refereegranskat)abstract
- Despite extensive breakthroughs in chemistry, molecular biology, and genetics in the last decades, the success rates of drug development projects remain low. To improve predictions of clinical efficacy and safety of new compounds, a plethora of 3D culture methods of human cells have been developed in which the cultured cells retain physiologically and functionally relevant phenotypes for multiple weeks. Here, we critically review current paradigms for organotypic cultures of human liver, gut, and kidney such as perfused microchips, spheroids, and hollow fiber bioreactors and discuss their utility for understanding drug pharmacokinetics, metabolism, and toxicity. Furthermore, bioprinting and the microfluidic integration of different tissue models to mimic systemic drug effects are highlighted as promising technological trends. In the last part of the review, we discuss important considerations regarding the choice of culture substratum material to limit adverse effects such as drug absorption while facilitating the phenotypic maintenance of cultured cells. We conclude that recent advances in organotypic and microphysiological culture models of human tissues can improve drug development and contribute to an amelioration of clinical attrition rates. However, further validation, benchmarking, and consolidation efforts are needed to achieve more widespread dissemination and eventually regulatory acceptance of these novel tools.
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