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Abstract Objective A mammalian Delta-Notch signaling component, Notch1, has been suggested for its expression during the normal sperm development although its conditional deletion caused no apparent abnormalities. Since we established our original transgenic mouse system that enabled labeling of past and ongoing Notch1 signaling at a cellular level, we tried to validate that observation in vivo. Our transgenic mouse system used Cre/loxP system to induce tandem dsRed expression upon Notch1 signaling. Results To our surprise, we were unable to observe tandem dsRed expression in the seminiferous tubules where the sperms developed. In addition, tandem dsRed expression was lacking in the somatic cells of the next generation in our transgenic mouse system, suggesting that sperms received no Notch1 signaling during their development. To validate this result, we conducted re-analysis of four single-cell RNA-seq datasets from mouse and human testes and showed that Notch1 expression was little in the sperm cell lineage. Collectively, our results posed a question into the involvement of Notch1 in the normal sperm development although this observation may help the interpretation of the previous result that Notch1 conditional deletion caused no apparent abnormalities in murine spermatogenesis.

Abstract Objective A Delta-Notch signaling component, Notch1, is involved in the normal development and multiple disorders of the kidney. Although the increase in Notch1 signaling is crucial to these pathogeneses, the basal signaling level in ‘healthy’ mature kidneys is still unclear. To address this question, we used an artificial Notch1 receptor fused with Gal4/UAS components in addition to the Cre/loxP system and fluorescent proteins in mice. This transgenic reporter mouse system enabled labeling of past and ongoing Notch1 signaling with tdsRed or Cre recombinase, respectively. Results We confirmed that our transgenic reporter mouse system mimicked the previously reported Notch1 signaling pattern. Using this successful system, we infrequently observed cells with ongoing Notch1 signaling only in Bowman’s capsule and tubules. We consider that Notch1 activation in several lines of disease model mice was pathologically significant itself.

Objective: A mammalian Delta-Notch signaling component, Notch1, has been suggested for its expression during the normal sperm development although its conditional deletion caused no apparent abnormalities. Since we established our original transgenic mouse system that enabled labeling of past and ongoing Notch1 signaling at a cellular level, we tried to validate that observation in vivo. Our transgenic mouse system used Cre/loxP system to induce tandem dsRed expression upon Notch1 signaling. Results: To our surprise, we were unable to observe tandem dsRed expression in the seminiferous tubules where the sperms developed. In addition, tandem dsRed expression was lacking in the somatic cells of the next generation in our transgenic mouse system, suggesting that sperms received no Notch1 signaling during their development. To validate this result, we conducted re-analysis of four single-cell RNA-seq datasets from mouse and human testes and showed that Notch1 expression was little in the sperm cell lineage. Collectively, our results posed a question into the involvement of Notch1 in the normal sperm development although this observation may help the interpretation of the previous result that Notch1 conditional deletion caused no apparent abnormalities in murine spermatogenesis. [ABSTRACT FROM AUTHOR]

Objective: A Delta-Notch signaling component, Notch1, is involved in the normal development and multiple disorders of the kidney. Although the increase in Notch1 signaling is crucial to these pathogeneses, the basal signaling level in 'healthy' mature kidneys is still unclear. To address this question, we used an artificial Notch1 receptor fused with Gal4/UAS components in addition to the Cre/loxP system and fluorescent proteins in mice. This transgenic reporter mouse system enabled labeling of past and ongoing Notch1 signaling with tdsRed or Cre recombinase, respectively. Results: We confirmed that our transgenic reporter mouse system mimicked the previously reported Notch1 signaling pattern. Using this successful system, we infrequently observed cells with ongoing Notch1 signaling only in Bowman's capsule and tubules. We consider that Notch1 activation in several lines of disease model mice was pathologically significant itself. [ABSTRACT FROM AUTHOR]

Abstract Objective Portal mesenchymal cells induce the epithelial differentiation of the bile ducts in the developing liver via one of the Delta-Notch signaling components, JAGGED1. Although this differential induction is crucial for normal liver physiology as its genetic disorder (Alagille syndrome) causes jaundice, the molecular mechanism behind JAGGED1 expression remains unknown. Here, we searched for upstream regulatory transcription factors of JAGGED1 using an integrated bioinformatics method. Results According to the DoRothEA database, which integrates multiple lines of evidence on the relationship between transcription factors and their downstream target genes, three transcription factors were predicted to be upstream of JAGGED1: SLUG, SOX2, and EGR1. Among these, SLUG and EGR1 were enriched in ACTA2-expressing portal mesenchymal cells in two previously reported human fetal liver single-cell RNA-seq datasets. JAGGED1-expressing portal mesenchymal cells tended to express SLUG rather than EGR1, supporting that SLUG induced JAGGED1 expression. Together with the higher confidentiality of SLUG (DoRothEA level A) over EGR1 (DoRothEA level D), we concluded that SLUG was one of the most important candidate transcription factors upstream of JAGGED1. These results add mechanistic insights into the developmental biology of how portal mesenchymal cells support biliary development in the liver.

Objective: Portal mesenchymal cells induce the epithelial differentiation of the bile ducts in the developing liver via one of the Delta-Notch signaling components, JAGGED1. Although this differential induction is crucial for normal liver physiology as its genetic disorder (Alagille syndrome) causes jaundice, the molecular mechanism behind JAGGED1 expression remains unknown. Here, we searched for upstream regulatory transcription factors of JAGGED1 using an integrated bioinformatics method. Results: According to the DoRothEA database, which integrates multiple lines of evidence on the relationship between transcription factors and their downstream target genes, three transcription factors were predicted to be upstream of JAGGED1: SLUG, SOX2, and EGR1. Among these, SLUG and EGR1 were enriched in ACTA2-expressing portal mesenchymal cells in two previously reported human fetal liver single-cell RNA-seq datasets. JAGGED1-expressing portal mesenchymal cells tended to express SLUG rather than EGR1, supporting that SLUG induced JAGGED1 expression. Together with the higher confidentiality of SLUG (DoRothEA level A) over EGR1 (DoRothEA level D), we concluded that SLUG was one of the most important candidate transcription factors upstream of JAGGED1. These results add mechanistic insights into the developmental biology of how portal mesenchymal cells support biliary development in the liver. [ABSTRACT FROM AUTHOR]

Abstract In this paper, an improved fractional-order model of boundary formation in the Drosophila large intestine dependent on Delta-Notch pathway is proposed for the first time. The uniqueness, nonnegativity, and boundedness of solutions are studied. In a two cells model, there are two equilibriums (no-expression of Delta and normal expression of Delta). Local asymptotic stability is proved for both cases. Stability analysis shows that the orders of the fractional-order differential equation model can significantly affect the equilibriums in the two cells model. Numerical simulations are presented to illustrate the conclusions. Next, the sensitivity of model parameters is calculated, and the calculation results show that different parameters have different sensitivities. The most and least sensitive parameters in the two cells model and the 60 cells model are verified by numerical simulations. What is more, we compare the fractional-order model with the integer-order model by simulations, and the results show that the orders can significantly affect the dynamic and the phenotypes.

In this paper, an improved fractional-order model of boundary formation in the Drosophila large intestine dependent on Delta-Notch pathway is proposed for the first time. The uniqueness, nonnegativity, and boundedness of solutions are studied. In a two cells model, there are two equilibriums (no-expression of Delta and normal expression of Delta). Local asymptotic stability is proved for both cases. Stability analysis shows that the orders of the fractional-order differential equation model can significantly affect the equilibriums in the two cells model. Numerical simulations are presented to illustrate the conclusions. Next, the sensitivity of model parameters is calculated, and the calculation results show that different parameters have different sensitivities. The most and least sensitive parameters in the two cells model and the 60 cells model are verified by numerical simulations. What is more, we compare the fractional-order model with the integer-order model by simulations, and the results show that the orders can significantly affect the dynamic and the phenotypes. [ABSTRACT FROM AUTHOR]

Background: The boundary formation in the Drosophila large intestine is widely studied as an important biological problem. It has been shown that the Delta-Notch signaling pathway plays an essential role in the formation of boundary cells. Results: In this paper, we propose a mathematical model for the Delta-Notch dependent boundary formation in the Drosophila large intestine in order to better interpret related experimental findings of this biological phenomenon. To achieve this, we not only perform stability analysis on the model from a theoretical point of view, but also perform numerical simulations to analyze the model with and without noises, the phenotype change with the change of Delta or Notch expression, and the perturbation influences of binding and inhibition parameters on the boundary formation. Conclusions: By doing all these work, we can assure that our model can better interpret the biological findings related to the boundary formation in the Drosophila large intestine. [ABSTRACT FROM AUTHOR]