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The Pax6 master control gene initiates spontaneous retinal development via a self-organising Turing network.

ABSTRACT: Understanding how complex organ systems are assembled from simple embryonic tissues is a major challenge. Across the animal kingdom a great diversity of visual organs are initiated by a 'master control gene' called Pax6, which is both necessary and sufficient for eye development. Yet precisely how Pax6 achieves this deeply homologous function is poorly understood. Using the chick as a model organism, we show that vertebrate Pax6 interacts with a pair of morphogen-coding genes, Tgfb2 and Fst, to form a putative Turing network, which we have computationally modelled. Computer simulations suggest that this gene network is sufficient to spontaneously polarise the developing retina, establishing the first organisational axis of the eye and prefiguring its further development. Our findings reveal how retinal self-organisation may be initiated independently of the highly ordered tissue interactions that help to assemble the eye in vivo These results help to explain how stem cell aggregates spontaneously self-organise into functional eye-cups in vitro We anticipate these findings will help to underpin retinal organoid technology, which holds much promise as a platform for disease modelling, drug development and regenerative therapies.

SUBMITTER: Grocott T

PROVIDER: S-EPMC7774904 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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The Pax6 master control gene initiates spontaneous retinal development via a self-organising Turing network.

Grocott Timothy T Lozano-Velasco Estefania E Mok Gi Fay GF Münsterberg Andrea E AE

Development (Cambridge, England) 20201223 24

Understanding how complex organ systems are assembled from simple embryonic tissues is a major challenge. Across the animal kingdom a great diversity of visual organs are initiated by a 'master control gene' called Pax6, which is both necessary and sufficient for eye development. Yet precisely how Pax6 achieves this deeply homologous function is poorly understood. Using the chick as a model organism, we show that vertebrate Pax6 interacts with a pair of morphogen-coding gene ...[more]

PMID: 33214222

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Project description:Endotherms such as rats and mice huddle together to keep warm. The huddle is considered to be an example of a self-organising system, because complex properties of the collective group behaviour are thought to emerge spontaneously through simple interactions between individuals. Groups of rodent pups display two such emergent properties. First, huddling undergoes a 'phase transition', such that pups start to aggregate rapidly as the temperature of the environment falls below a critical temperature. Second, the huddle maintains a constant 'pup flow', where cooler pups at the periphery continually displace warmer pups at the centre. We set out to test whether these complex group behaviours can emerge spontaneously from local interactions between individuals. We designed a model using a minimal set of assumptions about how individual pups interact, by simply turning towards heat sources, and show in computer simulations that the model reproduces the first emergent property--the phase transition. However, this minimal model tends to produce an unnatural behaviour where several smaller aggregates emerge rather than one large huddle. We found that an extension of the minimal model to include heat exchange between pups allows the group to maintain one large huddle but eradicates the phase transition, whereas inclusion of an additional homeostatic term recovers the phase transition for large huddles. As an unanticipated consequence, the extended model also naturally gave rise to the second observed emergent property--a continuous pup flow. The model therefore serves as a minimal description of huddling as a self-organising system, and as an existence proof that group-level huddling dynamics emerge spontaneously through simple interactions between individuals. We derive a specific testable prediction: Increasing the capacity of the individual to generate or conserve heat will increase the range of ambient temperatures over which adaptive thermoregulatory huddling will emerge.

Project description:BackgroundDecision-making in mental health systems should be supported by the evidence-informed knowledge transfer of data. Since mental health systems are inherently complex, involving interactions between its structures, processes and outcomes, decision support systems (DSS) need to be developed using advanced computational methods and visual tools to allow full system analysis, whilst incorporating domain experts in the analysis process. In this study, we use a DSS model developed for interactive data mining and domain expert collaboration in the analysis of complex mental health systems to improve system knowledge and evidence-informed policy planning.MethodsWe combine an interactive visual data mining approach, the self-organising map network (SOMNet), with an operational expert knowledge approach, expert-based collaborative analysis (EbCA), to develop a DSS model. The SOMNet was applied to the analysis of healthcare patterns and indicators of three different regional mental health systems in Spain, comprising 106 small catchment areas and providing healthcare for over 9 million inhabitants. Based on the EbCA, the domain experts in the development team guided and evaluated the analytical processes and results. Another group of 13 domain experts in mental health systems planning and research evaluated the model based on the analytical information of the SOMNet approach for processing information and discovering knowledge in a real-world context. Through the evaluation, the domain experts assessed the feasibility and technology readiness level (TRL) of the DSS model.ResultsThe SOMNet, combined with the EbCA, effectively processed evidence-based information when analysing system outliers, explaining global and local patterns, and refining key performance indicators with their analytical interpretations. The evaluation results showed that the DSS model was feasible by the domain experts and reached level 7 of the TRL (system prototype demonstration in operational environment).ConclusionsThis study supports the benefits of combining health systems engineering (SOMNet) and expert knowledge (EbCA) to analyse the complexity of health systems research. The use of the SOMNet approach contributes to the demonstration of DSS for mental health planning in practice.

Project description:PurposeA previous study demonstrated that CTCF (CCCTC binding factor) regulates homeobox Pax6 gene expression in early embryonic stages and plays a dominant role in eye development. The purpose of the present study was to explore further the mechanism of CTCF controlling Pax6 gene expression in human retinoblastoma (Rb) cells and in the development of chicken and mouse retinas.MethodsNorthern and Western analyses were used to detect expressions of CTCF and Pax6 in Rb cells. Pax6 transcription reporter and deletion mutants were used to study the regulatory interaction between CTCF and Pax6 in Rb cells and in the retina of chicken embryos. CTCF transgenic chicken embryos and mice were established by lipofection and microinjection of linearized cytomegalovirus (CMV)-CTCF construct into fertilized eggs and mouse oocytes, respectively. Injected oocytes were implanted in the uterus of foster mothers through microinjection into the ovarian duct. The expression of CTCF and Pax6 was determined in embryo sections by immunochemistry.ResultsStimulation of Rb cells with 10% FBS resulted in an increase in CTCF expression and a decrease in Pax6 expression. To study the regulatory mechanism, the Pax6 reporter and its deletion mutant activities were determined in transfected Rb cells and chicken embryonic retinas, revealing that CTCF interacts with the Pax6 gene in Rb cells through transcription control in the 5'-flanking region upstream from the Pax6 P0 promoter. Overexpression of CTCF in Rb cells suppressed Pax6 reporter activity and downregulated endogenous Pax6 expression. In contrast, downregulation of CTCF expression by knockdown of CTCF mRNA using specific small interfering (si)RNA markedly enhanced Pax6 expression in Rb cells. Further study in CTCF transgenic mouse embryos verified that overexpression of CTCF suppressed Pax6 gene expression in the retina.ConclusionsCTCF plays an important role in regulating Pax6 expression in Rb cells and in the developmental retina, and the regulation of Pax6 gene expression by CTCF in the retina is through transcriptional regulation.

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The Pax6 master control gene initiates spontaneous retinal development via a self-organising Turing network.

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The <i>Pax6</i> master control gene initiates spontaneous retinal development via a self-organising Turing network.

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