Theory of Robustness of Irreversible Differentiation in a Stem Cell System: Chaos hypothesis

Based on extensive study of a dynamical systems model of the development of a cell society, a novel theory for stem cell differentiation and its regulation is proposed as the ``chaos hypothesis''. Two fundamental features of stem cell systems - stochastic differentiation of stem cells and the robustness of a system due to regulation of this differentiation - are found to be general properties of a system of interacting cells exhibiting chaotic intra-cellular reaction dynamics and cell division, whose presence does not depend on the detail of the model. It is found that stem cells differentiate into other cell types stochastically due to a dynamical instability caused by cell-cell interactions, in a manner described by the Isologous Diversification theory. This developmental process is shown to be stable not only with respect to molecular fluctuations but also with respect to removal of cells. With this developmental process, the irreversible loss of multipotency accompanying the change from a stem cell to a differentiated cell is shown to be characterized by a decrease in the chemical diversity in the cell and of the complexity of the cellular dynamics. The relationship between the division speed and this loss of multipotency is also discussed. Using our model, some predictions that can be tested experimentally are made for a stem cell system.Comment: 31 pages, 10 figures, submitted to Jour. Theor. Bio

The Caenorhabditis elegans vulva: A post-embryonic gene regulatory network controlling organogenesis

The Caenorhabditis elegans vulva is an elegant model for dissecting a gene regulatory network (GRN) that directs postembryonic organogenesis. The mature vulva comprises seven cell types (vulA, vulB1, vulB2, vulC, vulD, vulE, and vulF), each with its own unique pattern of spatial and temporal gene expression. The mechanisms that specify these cell types in a precise spatial pattern are not well understood. Using reverse genetic screens, we identified novel components of the vulval GRN, including nhr-113 in vulA. Several transcription factors (lin-11, lin-29, cog-1, egl-38, and nhr-67) interact with each other and act in concert to regulate target gene expression in the diverse vulval cell types. For example, egl-38 (Pax2/5/8) stabilizes the vulF fate by positively regulating vulF characteristics and by inhibiting characteristics associated with the neighboring vulE cells. nhr-67 and egl-38 regulate cog-1, helping restrict its expression to vulE. Computational approaches have been successfully used to identify functional cis-regulatory motifs in the zmp-1 (zinc metalloproteinase) promoter. These results provide an overview of the regulatory network architecture for each vulval cell type

Cell division and migration in a 'genotype' for neural networks

Much research has been dedicated recently to applying genetic algorithms to populations of neural networks. However, while in real organisms the inherited genotype maps in complex ways into the resulting phenotype, in most of this research the development process that creates the individual phenotype is ignored. In this paper we present a model of neural development which includes cell division and cell migration in addition to axonal growth and branching. This reflects, in a very simplified way, what happens in the ontogeny of real organisms. The development process of our artificial organisms shows successive phases of functional differentiation and specialization. In addition, we find that mutations that affect different phases of development have very different evolutionary consequences. A single change in the early stages of cell division/migration can have huge effects on the phenotype while changes in later stages have usually a less drammatic impact. Sometimes changes that affect the first developental stages may be retained producing sudden changes in evolutionary history

Segmentally homologous neurons acquire two different terminal neuropeptidergic fates in the Drosophila nervous system

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. In this study, we identify the means by which segmentally homologous neurons acquire different neuropeptide fates in Drosophila. Ventral abdominal (Va)-neurons in the A1 segment of the ventral nerve cord express DH31 and AstA neuropeptides (neuropeptidergic fate I) by virtue of Ubx activity, whereas the A2-A4 Va-neurons express the Capa neuropeptide (neuropeptidergic fate II) under the influence of abdA. These different fates are attained through segment-specific programs of neural subtype specification undergone by segmentally homologous neurons. This is an attractive alternative by which Hox genes can shape Drosophila segmental neural architecture (more sophisticated than the previously identified binary “to live” or “not to live” mechanism). These data refine our knowledge of the mechanisms involved in diversifying neuronal identity within the central nervous systemThis study was supported by grant number: BFU2013-43858-

The MobyDick Project: A Mobile Heterogeneous All-IP Architecture

Proceedings of Advanced Technologies, Applications and Market Strategies for 3G (ATAMS 2001). Cracow, Poland: 17-20 June, 2001.This paper presents the current stage of an IP-based architecture for heterogeneous environments, covering UMTS-like W-CDMA wireless access technology, wireless and wired LANs, that is being developed under the aegis of the IST Moby Dick project. This architecture treats all transmission capabilities as basic physical and data-link layers, and attempts to replace all higher-level tasks by IP-based strategies. The proposed architecture incorporates aspects of mobile-IPv6, fast handover, AAA-control, and Quality of Service. The architecture allows for an optimised control on the radio link layer resources. The Moby dick architecture is currently under refinement for implementation on field trials. The services planned for trials are data transfer and voice-over-IP.Publicad

Transcriptional repressor ZEB2 promotes terminal differentiation of CD8⁺ effector and memory T cell populations during infection

ZEB2 is a multi-zinc-finger transcription factor known to play a significant role in early neurogenesis and in epithelial-mesenchymal transition-dependent tumor metastasis. Although the function of ZEB2 in T lymphocytes is unknown, activity of the closely related family member ZEB1 has been implicated in lymphocyte development. Here, we find that ZEB2 expression is up-regulated by activated T cells, specifically in the KLRG1(hi) effector CD8(+) T cell subset. Loss of ZEB2 expression results in a significant loss of antigen-specific CD8(+) T cells after primary and secondary infection with a severe impairment in the generation of the KLRG1(hi) effector memory cell population. We show that ZEB2, which can bind DNA at tandem, consensus E-box sites, regulates gene expression of several E-protein targets and may directly repress Il7r and Il2 in CD8(+) T cells responding to infection. Furthermore, we find that T-bet binds to highly conserved T-box sites in the Zeb2 gene and that T-bet and ZEB2 regulate similar gene expression programs in effector T cells, suggesting that T-bet acts upstream and through regulation of ZEB2. Collectively, we place ZEB2 in a larger transcriptional network that is responsible for the balance between terminal differentiation and formation of memory CD8(+) T cells

Developmental motifs reveal complex structure in cell lineages

Many natural and technological systems are complex, with organisational structures that exhibit characteristic patterns, but defy concise description. One effective approach to analysing such systems is in terms of repeated topological motifs. Here, we extend the motif concept to characterise the dynamic behaviour of complex systems by introducing developmental motifs, which capture patterns of system growth. As a proof of concept, we use developmental motifs to analyse the developmental cell lineage of the nematode Caenorhabditis elegans, revealing a new perspective on its complex structure. We use a family of computational models to explore how biases arising from the dynamics of the developmental gene network, as well as spatial and temporal constraints acting on development, contribute to this complex organisation