Functional distinction in oncogenic Ras variant activity in Caenorhabditis elegans.

Ras genes are important oncogenes that are frequently mutated in cancer. Human oncogenic variants exhibit functional distinctions in terms of their representation in different cancer types, impact on cellular targets and sensitivity to pharmacological treatments. However, how these distinct variants influence and respond to the cellular networks in which they are embedded is poorly understood.

Gene duplication and evolutionary plasticity of lin-12/Notch gene function in Caenorhabditis.

Gene duplication is an important substrate for the evolution of new gene functions, but the impacts of gene duplicates on their own activities and on the developmental networks in which they act are poorly understood. Here, we use a natural experiment of lin-12/Notch gene duplication within the nematode genus Caenorhabditis, combined with characterization of loss- and gain-of-function mutations, to uncover functional distinctions between the duplicate genes in 1 species (Caenorhabditis briggsae) and their single-copy ortholog in Caenorhabditis elegans. First, using improved genomic sequence and gene model characterization, we confirm that the C.

Efficient parameter generation for constrained models using MCMC.

Mathematical models of complex systems rely on parameter values to produce a desired behavior. As mathematical and computational models increase in complexity, it becomes correspondingly difficult to find parameter values that satisfy system constraints. We propose a Markov Chain Monte Carlo (MCMC) approach for the problem of constrained model parameter generation by designing a Markov chain that efficiently explores a model's parameter space.

Genetic characterization of C. elegans TMED genes.

Background: p24/transmembrane Emp24 domain (TMED) proteins are a set of evolutionarily conserved, single pass transmembrane proteins that have been shown to facilitate protein secretion and selection of cargo proteins to transport vesicles in the cellular secretion pathway. However, their functions in animal development are incompletely understood.

Results: The C.

Discovery of nonautonomous modulators of activated Ras.

Communication between mesodermal cells and epithelial cells is fundamental to normal animal development and is frequently disrupted in cancer. However, the genes and processes that mediate this communication are incompletely understood. To identify genes that mediate this communication and alter the proliferation of cells with an oncogenic Ras genotype, we carried out a tissue-specific genome-wide RNAi screen in Caenorhabditis elegans animals bearing a let-60(n1046gf) (RasG13E) allele.

Coordination of local and long range signaling modulates developmental patterning.

The development of multicellular organisms relies on correct patterns of cell fates to produce functional tissues in the mature organism. A commonly observed developmental pattern consists of alternating cell fates, where neighboring cells take on distinct cell fates characterized by contrasting gene and protein expression levels, and this cell fate pattern repeats over two or more cells. The patterns produced by these fate decisions are regulated by a small number of highly conserved signaling networks, some of which are mediated by long range diffusible signals and others mediated by local contact-dependent signals.

Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma.

Androgen Receptor (AR) signaling is a critical driver of hormone-dependent prostate cancer and has also been proposed to have biological activity in female hormone-dependent cancers, including type I endometrial carcinoma (EMC). In this study, we evaluated the preclinical efficacy of a third-generation AR antagonist, enzalutamide, in a genetic mouse model of EMC, Sprr2f-Cre;Pten. In this model, ablation of Pten in the uterine epithelium leads to localized and distant malignant disease as observed in human EMC.

Evolution of Transcriptional Repressors Impacts Caenorhabditis Vulval Development.

Comparative genomic sequence analysis has found that the genes for many chromatin-associated proteins are poorly conserved, but the biological consequences of these sequence changes are not understood. Here, we show that four genes identified for an Inappropriate Vulval cell Proliferation (ivp) phenotype in the nematode Caenorhabditis briggsae exhibit distinct functions and genetic interactions when compared with their orthologs in C. elegans.

EGL-38/Pax coordinates development in the Caenhorhabditis elegans egg-laying system through EGF pathway dependent and independent functions.

Paired box (Pax) proteins function as regulators of coordinated development in organogenesis by controlling factors such as cell growth and differentiation necessary to organize multiple cell types into a single, cohesive organ. Previous work has suggested that Pax transcription factors may regulate diverse cell types through participation in inductive cell-to-cell signaling, which has not been well explored. Here we show that EGL-38, a Pax2/5/8 ortholog, coordinates differentiation of the C.

FACT complex gene duplicates exhibit redundant and non-redundant functions in C. elegans.

FACT (facilitates chromatin transcription) is a histone chaperone complex important in genomic processes including transcription, DNA replication, and DNA repair. FACT is composed of two proteins, SSRP1 and SPT16, which are highly conserved across eukaryotes. While the mechanisms for FACT in nucleosome reorganization and its relationship to DNA processes is well established, how these roles impact coordination in multicellular animal development are less well understood.

Discovery of Stromal Regulatory Networks that Suppress Ras-Sensitized Epithelial Cell Proliferation.

Mesodermal cells signal to neighboring epithelial cells to modulate their proliferation in both normal and disease states. We adapted a Caenorhabditis elegans organogenesis model to enable a genome-wide mesodermal-specific RNAi screen and discovered 39 factors in mesodermal cells that suppress the proliferation of adjacent Ras pathway-sensitized epithelial cells. These candidates encode components of protein complexes and signaling pathways that converge on the control of chromatin dynamics, cytoplasmic polyadenylation, and translation.

Differing roles for sur-2/MED23 in C. elegans and C. briggsae vulval development.

Normal vulval development in the nematode Caenorhabditis briggsae is identical to that in the related Caenorhabditis elegans. However, several experiments suggest that there are differences between the two species with respect to the contribution of EGF/Ras signaling. To investigate these differences genetically, we have characterized a C.

A computational model predicts genetic nodes that allow switching between species-specific responses in a conserved signaling network.

Cell signaling networks regulate a variety of developmental and physiological processes, and changes in their response to external stimuli are often implicated in disease initiation and progression. To elucidate how different responses can arise from conserved signaling networks, we have developed a mathematical model of the well-characterized Caenorhabditis vulval development network involving EGF, Wnt and Notch signaling that recapitulates biologically observed behaviors. We experimentally block a specific element of the EGF pathway (MEK), and find different behaviors in vulval development in two Caenorhabditis species, C.

Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo.

Inactivation of phosphatase and tensin homology deleted on chromosome 10 (PTEN) is linked to increased PI3K-AKT signaling, enhanced organismal growth, and cancer development. Here we generated and analyzed Pten knock-in mice harboring a C2 domain missense mutation at phenylalanine 341 (Pten(FV)), found in human cancer. Despite having reduced levels of PTEN protein, homozygous Pten(FV/FV) embryos have intact AKT signaling, develop normally, and are carried to term.

Mutations in Caenorhabditis briggsae identify new genes important for limiting the response to EGF signaling during vulval development.

Studies of vulval development in the nematode C. elegans have identified many genes that are involved in cell division and differentiation processes. Some of these encode components of conserved signal transduction pathways mediated by EGF, Notch, and Wnt.

A regulatory network modeled from wild-type gene expression data guides functional predictions in Caenorhabditis elegans development.

Background: Complex gene regulatory networks underlie many cellular and developmental processes. While a variety of experimental approaches can be used to discover how genes interact, few biological systems have been systematically evaluated to the extent required for an experimental definition of the underlying network. Therefore, the development of computational methods that can use limited experimental data to define and model a gene regulatory network would provide a useful tool to evaluate many important but incompletely understood biological processes.

Developmental functions for the Caenorhabditis elegans Sp protein SPTF-3.

Sp factors are important for animal development and the transcriptional regulation of a wide variety of genes. How they influence the developmental decisions of individual cells within the organism, however, is poorly understood. To better understand the developmental functions for Sp transcription factors, we have characterized the functions of Caenorhabditis elegans SPTF-3 using RNAi knockdown and a non-null, hypomorphic mutant allele.

Caenorhabditis briggsae recombinant inbred line genotypes reveal inter-strain incompatibility and the evolution of recombination.

The nematode Caenorhabditis briggsae is an emerging model organism that allows evolutionary comparisons with C. elegans and exploration of its own unique biological attributes. To produce a high-resolution C.

C. elegans select.

The technical toolkit for Caenorhabditis elegans expands to include experimental selection using antibiotic resistance genes.

A toolkit for rapid gene mapping in the nematode Caenorhabditis briggsae.

Background: The nematode C. briggsae serves as a useful model organism for comparative analysis of developmental and behavioral processes. The amenability of C.

Coordinate regulation of gene expression in the C. elegans excretory cell by the POU domain protein CEH-6.

Excretory renal organs are critical in animals for osmoregulation and the elimination of waste. Renal organs across a range of species exhibit cellular and molecular similarities. For example, class III POU-homeodomain transcription factors are expressed in the renal organs of many invertebrates and vertebrates.

HOM-C genes, Wnt signaling and axial patterning in the C. elegans posterior ventral epidermis.

Wnt signaling and HOM-C/Hox genes pattern cell fate along the anterior/posterior axis in many animals. In general, Wnt signaling participates in establishing the anterior/posterior axis, whereas HOM-C genes confer regional identities to cells along the axis. However, recent work in non-bilaterial metazoans suggests that the ancestral patterning system relied on Wnts, with a later co-option of HOM-C genes to replace Wnts in regional patterning.

The Caenorhabditis elegans heterochronic gene lin-14 coordinates temporal progression and maturation in the egg-laying system.

Heterochronic genes function to ensure the timing of stage-specific developmental events in C. elegans. Mutations in these genes cause certain developmental programs to be executed in a precocious or retarded manner.

Positive and negative regulatory inputs restrict pax-6/vab-3 transcription to sensory organ precursors in Caenorhabditis elegans.

The Pax-6 gene encodes a transcription factor essential for the development of eyes and other sensory organs in species ranging from planaria to mice. Because Pax-6 activity can be both necessary and sufficient for eye organogenesis, much work has focused on PAX-6 function and regulation of target genes. However, less is known about the genetic mechanisms that establish the Pax-6 expression pattern.