Biological cell networks exhibit complex combinations of both discrete and continuous behaviors: indeed, the dynamics that govern the spatial and temporal increase or decrease of protein concentration inside a single cell are continuous di#erential equations, while the activation or deactivation of these continuous dynamics are triggered by discrete switches which encode protein concentrations reaching given thresholds. In this paper, we model as a hybrid system a striking example of this behavior in a biological mechanism called Delta-Notch signaling, which is thought to be the primary mechanism of cell di#erentiation in a variety of cell networks. We present results in both simulation and reachability analysis of this hybrid system. We emphasize how the hybrid system model is computationally superior (for both simulation and analysis) to other nonlinear models in the literature, without compromising faithful modeling of the biological phenomena. 1

Knowledge genetic control segmentation Drosophila made insect segmentation paradigmatic case the study evolution developmental mechanisms. Drosophila the patterns expression segmentation genes established simultaneously segments a complex interactions between transcriptional factors that diffuse in a syncytium occupying whole embryo. Such mechanisms cannot short germ-band insects where segments appear sequentially from a cellularized posterior proliferative zone. Here compare mechanisms segmentation different organisms and discuss how the transition between different types segmentation explained small and progressive changes the underlying gene networks. The recent discovery a temporal oscillation expression vertebrate homologs pair rule gene hairy during somitogenesis enhances plausibility of earlier proposal evolutionary origin both short and long germ band modes segmentation was oscillatory genetic network (Newman, 1993). implication scenario that self-organizing pattern forming ...

Stem cells in the basal layer of human interfollicular epidermis form clusters that can be reconstituted in vitro. In order to supply the interfollicular epidermis with differentiated cells, the size of these clusters must be controlled. Evidence suggests that control is regulated via differentiation of stem cells on the periphery of the clusters. Moreover, there is growing evidence that this regulation is mediated by the Notch signalling pathway. In this paper, we develop theoretical arguments, in conjunction with computer simulations of a model of the basal layer, to show that regulation of differentiation is the most likely mechanism for cluster control. In addition, we show that stem cells must adhere more strongly to each other than they do to differentiated cells. Developing our model further we show that lateral-induction, mediated by the Notch signalling pathway, is a natural mechanism for cluster control. It can not only indicate to cells the size of the cluster they are in and their position within it, but it can also control the cluster size. This can only be achieved by postulating a secondary, cluster wide, differentiation signal, and cells with high Delta expression being deaf to this signal.

I would like to first start off by thanking my thesis advisor, Steve DiNardo. He is the epitome of a great advisor. His relaxed style, patience, penchant for teaching, handson instruction, willingness to listen, and ability to offer constructive criticism were instrumental in helping me grow into the scientist that I am today. He has provided an engaging lab environment where knowledge is shared openly and where scientific rigor is encouraged. In addition, I would like to thank the members of my thesis committee: Meera Sundaram, Aaron Gitler, Warren Pear and Amin Ghabrial. Your critical input and expertise were invaluable in the successful completion of my thesis work. I am also grateful for a host of mentors who have believed and invested in me over the years. I know that without their guidance, I would not be here today. From Mrs. Dillard, my 6 th grade science teacher, who officially made me fall in love with Science to Mr. Forbes and Mr. Hostage, my high school Chemistry teachers, whose instruction

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Research article On the role of the MAGUK proteins encoded by Drosophila varicose during embryonic and postembryonic development

Research article Notch signaling through Tramtrack bypasses the mitosis promoting activity of the JNK pathway in the mitotic-to-endocycle transition of

In mammals, six separate sensory regions in the inner ear are essential for hearing and balance function. Each sensory region is made up of hair cells, which are the sensory cells, and their associated supporting cells, both arising from a common progenitor. Little is known about the molecular mechanisms that govern the development of these sensory organs. Notch signaling plays a pivotal role in the differentiation of hair cells and supporting cells by mediating lateral inhibition via the ligands Delta-like 1 and Jagged (JAG) 2. However, another Notch ligand, JAG1, is expressed early in the sensory patches prior to cell differentiation, indicating that there may be an earlier role for Notch signaling in sensory development in the ear. Here, using conditional gene targeting, we show that the Jag1 gene is required for the normal development of all six sensory organs within the inner ear. Cristae are completely lacking in Jag1-conditional knockout (cko) mutant inner ears, whereas the cochlea and utricle show partial sensory development. The saccular macula is present but malformed. Using SOX2 and p27 kip1 as molecular markers of the prosensory domain, we show that JAG1 is initially expressed in all the prosensory regions of the ear, but becomes down-regulated in the nascent organ of Corti by embryonic day 14.5, when the cells exit the cell cycle and differentiate. We also show that both SOX2 and p27 kip1 are down-regulated in Jag1-cko inner ears. Taken together, these data demonstrate that JAG1 is expressed early in the prosensory domains of both the cochlear and vestibular regions, and is required to maintain the normal expression levels of both SOX2 and p27 kip1. These data demonstrate that JAG1-mediated Notch signaling is essential during early development for establishing the prosensory regions of the inner ear. Citation: Kiernan AE, Xu J, Gridley T (2006) The Notch ligand JAG1 is required for sensory progenitor development in the mammalian inner ear. PLoS Genet 2(1): e4.

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