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The soil bacterium, Myxococcus xanthus initiates a developmental program when nutrients are limited. This results in the formation of a multicellular fruiting body structure filled with differentiated, environmentally resistant spores. At least four cell-cell signals, cell motility, and aggregation functions are required for the completion of fruiting body formation.
Phylogenetic analyses and sequence surveys of developmental regulator gene families indicate that two large-scale gene duplications, most likely genome duplications, occurred in ancestors of vertebrates. Relaxed constraints allowed duplicated and thus redundant genes to diverge in a two stage mechanism. Neutral changes dominated at first but then positively selected regulatory changes evolved the novel and increasingly complex vertebrate developmental program.
Comparisons between the cell lineages of different nematode species reveal the flexibility of developmental programs over evolutionary time.
Hox proteins shape animal structures by eliciting different developmental programs along the anteroposterior body axis. A recent study reveals that the Drosophila Hox protein Deformed directly activates the cell-death-promoting gene reaper to maintain the boundaries between distinct head segments.
BACKGROUND: Three principal genes are involved in developmental programmed cell death (PCD) in the nematode worm Caenorhabditis elegans. The ced-3 and ced-4 genes are both required for each PCD, whereas ced-9 acts to prevent the death-promoting actions of these genes in cells that are destined to survive. Vertebrate homologues of both ced-3 and ced-9 have been identified as the genes encoding the caspase cysteine proteases and the Bcl-2 family, respectively. In contrast, no vertebrate homologue of ced-4 is known. The CED-3/caspases are important effectors of apoptosis that are presumed to act by cleaving specific target substrates. However, the molecular functions of the CED-9/Bcl-2 and CED-4 proteins are unknown. The unicellular yeast Schizosaccharomyces pombe shares many general cellular properties with metazoa, but has no identified cell suicide machinery. We have therefore used S. pombe as a naive model cell system in which to examine the biological effects of cell-death proteins. RESULTS: Induction of wild-type ced-4 expression in S. pombe resulted in rapid focal chromatin condensation and lethality. Mutation of the putative nucleotide-binding P-loop motif of CED-4 (K165Q) eliminated the lethal phenotype. Immunolocalization of CED-4 to the condensed chromatin suggested that the phenotype may result from an intrinsic activity of CED-4. Co-expression of ced-9 prevented CED-4-induced chromatin condensation and lethality, and caused the relocalization of CED-4 to endoplasmic reticulum and outer mitochondrial membranes. A direct interaction between CED-4 and CED-9 was confirmed by yeast two-hybrid analysis. CONCLUSIONS: Using S. pombe as a model system in which to assay CED-4 function, we have identified a potential direct role for CED-4 in chromatin condensation. Chromatin condensation is a ubiquitous feature of metazoan apoptosis that has yet to be linked to an effector. The CED-9-mediated rescue of CED-4-induced lethality in this system and the interaction of the two proteins in the yeast two-hybrid analysis suggest that CED-9 inhibits CED-4 action by direct physical association.
Recent studies in human cells and in the yeast Yarrowia lipolytica have shown that peroxisomes consist of numerous structurally distinct subcompartments that differ in their import competency for various proteins and are related through a time-ordered conversion of one subcompartment to another. Our studies have implicated the fusion of small peroxisomal precursors as an early event in the multistep assembly of peroxisomes operating in Y. lipolytica. Newly discovered unexpected roles for peroxisomes in specific developmental programs have expanded the remarkable plasticity of peroxisomal functions. Here, we highlight recent discoveries on the highly dynamic nature of peroxisome assembly and function and suggest questions for future research in these areas.
A novel extracellular ligand-binding domain, termed CHASE, is described in sensory adenylyl and diguanylate cyclases, and histidine kinases, in several bacterial species, Dictyostelium and plants. The CHASE domain is predicted to sense stimuli that are specific for the developmental program of an organism.
End-stage renal disease (ESRD) care is sustaining the lives of over 300,000 individuals today, but with a quality of life and life expectancy that is less than desirable. Nearly 500,000 individuals will be ESRD patients in the year 2005. Will they receive better ESRD care in 2005 than patients receive today? ESRD care modalities are examined in terms of effectiveness (quality of life and life expectancy), accessibility, and affordability from the patient's perspective. Developmental programs with potential to improve ESRD care within the next 5 years are reviewed for potential impact on effectiveness, accessibility, and affordability. The potential effects of global capitation on the quality of ESRD care and the successful development of advanced renal replacement therapies are also examined.
Two important Ras-guanyl nucleotide exchange factors, Sos and RasGRP1, control Ras activation in thymocytes. However, the relative contribution of these two exchange factors to Ras/ERK activation and their resulting impact on positive and negative selection is unclear. We have produced two lines of RasGRP1(-/-) TCR transgenic mice to determine the effect of RasGRP1 in T cell development under conditions of defined TCR signaling. Our results demonstrate that RasGRP1 is crucial for thymocytes expressing weakly selecting TCRs whereas those that express stronger selecting TCRs are more effective at utilizing RasGRP1-independent mechanisms for ERK activation and positive selection. Analysis of RasGRP1(-/-) peripheral T cells also revealed hitherto unidentified functions of RasGRP1 in regulating T cell homeostasis and sustaining antigen-induced developmental programming.
The T cell compartment is continuously replenished by a renewable source of stem cells. In the adult, bone marrow-derived stem cells seed the thymus and initiate a developmental program that requires a series of incompletely understood signals that are normally provided by the thymus. Failure to recapitulate this process in simple in vitro cultures has hampered efforts to fully characterize these unique signals. In this issue of Immunity, Schmitt and Zúñiga-Pflücker describe a simple in vitro culture system that is able to generate mature T cells from fetal liver stem cells by expressing the Notch ligand Delta-1 on the OP9 stromal cell line. This finding should greatly enhance efforts to study T cell development and may provide a tool for generating defined T cell populations in vitro.
Bcl-2 family members that have only a single Bcl-2 homology domain, BH3, are potent inducers of apoptosis, and some appear to play a critical role in developmentally programmed cell death. We examined the regulation of the proapoptotic activity of the BH3-only protein Bim. In healthy cells, most Bim molecules were bound to LC8 cytoplasmic dynein light chain and thereby sequestered to the microtubule-associated dynein motor complex. Certain apoptotic stimuli disrupted the interaction between LC8 and the dynein motor complex. This freed Bim to translocate together with LC8 to Bcl-2 and to neutralize its antiapoptotic activity. This process did not require caspase activity and therefore constitutes an initiating event in apoptosis signaling.
The major water-soluble proteins (crystallins) responsible for the optical properties of the cellular lenses of vertebrates and invertebrates are surprisingly diverse and often differ among species (i.e., are taxon-specific). Many crystallins are encoded by the identical gene specifying a stress protein or a metabolic enzyme which has non-refractive functions in numerous tissues. This double use of a distinct protein has been called gene sharing. Abundant expression of various metabolic enzymes also occurs in a taxon-specific manner in corneal epithelial cells, suggesting that gene sharing extends to this transparent tissue. It has been proposed that one of the most abundant corneal enzymes (aldehyde dehydrogenase class 3) may protect the eye by directly absorbing ultraviolet light, as well as by providing an enzymatic function. It also seems possible that the high expression of corneal enzymes (5-40% of the water-soluble proteins) may reduce scattering in the corneal epithelium by minimizing spatial fluctuations in refractive index as they do in the lens. Thus, gene sharing may be a widespread phenomenon encompassing the lens, cornea and probably other systems. Lens-preferred expression of crystallin genes is integrated in a complex developmental program utilizing in many cases Pax-6. The differential expression of alpha B-crystallin (a small heat shock protein) in different tissues involves the combinatorial use of both shared and lens-specific cis-control elements. Corneal-preferred gene expression appears to depend in part on induction by environmental influences. Among the implications of gene sharing are that gene duplication is not required for the evolution of a new protein phenotype, a change in gene regulation is sufficient, that proteins may be under more than one selective constraint, affecting their evolutionary clock, and that it would be prudent to consider the possibility that any given gene may have important, unrecognized roles when planning to implement gene therapy in the future.
Most angiosperm flowers are tightly integrated, functionally bisexual shoots that have carpels with enclosed ovules. Flowering plants evolved from within the gymnosperms, which lack this combination of innovations. Paradoxically, phylogenetic reconstructions suggest that the flowering plant lineage substantially pre-dates the evolution of flowers themselves. We provide a model based on known gene regulatory networks whereby positive selection on a single, partially redundant gene duplicate 'trapped' the ancestors of flower-bearing plants into the condensed, bisexual state approximately 130 million years ago. The LEAFY (LFY) gene of Arabidopsis encodes a master regulator that functions as the main conduit of environmental signals to the reproductive developmental program. We directly link the elimination of one LFY paralog, pleiotropically maintained in gymnosperms, to the sudden appearance of flowers in the fossil record.
During seed development, coordinated developmental programs lead to the formation of the embryo, endosperm and seed coat. The maternal effects of the genes affected in the fertilisation-independent seed class of mutants play an important role in seed development. The plant Polycomb proteins MEDEA and FERTILIZATION-INDEPENDENT ENDOSPERM physically interact and form a complex, in a manner similar to that of their counterparts in animals. Maternal-effect phenotypes can result from regulation by genomic imprinting, a phenomenon of critical importance for both sexual and apomictic seed development.
The plant vascular system plays a pivotal role in the delivery of nutrients to distantly located organs. Recent discoveries have provided new insight into a novel role for plasmodesmata and the phloem in terms of the transport and delivery of information macromolecules (i.e. proteins and ribonucleoprotein complexes). Non-cell/organ-autonomous control over gene expression may function both in defense signaling and developmental programming in plants.
Biotrophic interfaces are formed in mutualistic and parasitic plant-fungus interactions. They result from coordinated developmental programs in both partners and represent specialized platforms for the exchange of information and nutritional metabolites. New data on the establishment and the components of functional interfaces have been obtained in a number of ways. First, by isolation of symbiotically defective mutants; second, by characterization of new genes and their products; and, third, by the identification and localization of components of biotrophic interfaces, such as cell-wall proteins, H+-ATPases and nutrient transporters.
Microarray expression profiling and the development of data-mining tools and new statistical instruments affords an unprecedented opportunity for the genome-scale study of bacterial pathogenicity. Expression profiles obtained from bacteria grown in media simulating host microenvironments yield a portrait of interacting metabolic pathways and multistage developmental programs and disclose regulatory networks. The analysis of closely related strains and species by microarray-based comparative genomics provides a measure of genetic variability within natural populations and identifies crucial differences between pathogen and commensal. In the near future, the combined use of bacterial and host microarrays to study the same infected tissue will reveal the host-pathogen dialogue in a gene-by-gene and site- and time-specific manner. This review discusses the use of microarray-based expression profiling to identify genes of pathogenic bacteria that are differentially regulated in response to host-specific signals. Additionally, the review describes the application of microarray methods to disclose differences in gene content between taxonomically related strains that vary with respect to pathogenic phenotype.
Recent studies have indicated that complement proteins might exert novel functions that are distinct from their well-established inflammatory role, by modulating cellular responses and cell-cell interactions that are crucial to early development and cell differentiation. Accumulating evidence suggests that complement might have important roles in diverse biologic processes, ranging from early hematopoiesis to skeletal and vascular development and normal reproduction. Furthermore, it is now becoming evident that complement-regulated pathways interact with other signaling networks and influence the outcome of complex developmental programs, such as limb regeneration in lower vertebrates and organ regeneration in mammals. These findings highlight a previously under-appreciated role of complement and might have important implications in the context of normal development by helping to elucidate the rather obscure role of innate immunity in such cell modulatory pathways.