Tight control of cell-cell communication is essential for the generation of a normally patterned embryo. A critical mediator of key cell-cell signaling events during embryogenesis is the highly conserved Wnt family of secreted proteins. Recent biochemical and genetic analyses have greatly enriched our understanding of how Wnts signal, and the list of canonical Wnt signaling components has exploded. The data reveal that multiple extracellular, cytoplasmic, and nuclear regulators intricately modulate Wnt signaling levels. In addition, receptor-ligand specificity and feedback loops help to determine Wnt signaling outputs. Wnts are required for adult tissue maintenance, and perturbations in Wnt signaling promote both human degenerative diseases and cancer. The next few years are likely to see novel therapeutic reagents aimed at controlling Wnt signaling in order to alleviate these conditions.

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The Wnt signaling pathway in development and disease.

Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Integrative Genomics Viewer

In the context of cancer diagnosis and treatment, we consider the problem of constructing an accurate prediction rule on the basis of a relatively small number of tumor tissue samples of known type containing the expression data on very many (possibly thousands) genes. Recently, results have been presented in the literature suggesting that it is possible to construct a prediction rule from only a few genes such that it has a negligible prediction error rate. However, in these results the test error or the leave-one-out cross-validated error is calculated without allowance for the selection bias. There is no allowance because the rule is either tested on tissue samples that were used in the first instance to select the genes being used in the rule or because the cross-validation of the rule is not external to the selection process; that is, gene selection is not performed in training the rule at each stage of the cross-validation process. We describe how in practice the selection bias can be assessed and corrected for by either performing a cross-validation or applying the bootstrap external to the selection process. We recommend using 10-fold rather than leave-one-out cross-validation, and concerning the bootstrap, we suggest using the so-called .632+ bootstrap error estimate designed to handle overfitted prediction rules. Using two published data sets, we demonstrate that when correction is made for the selection bias, the cross-validated error is no longer zero for a subset of only a few genes.

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Selection bias in gene extraction on the basis of microarray gene-expression data.

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Role of WHO.

Marine sponges often contain diverse and abundant microbial communities, including bacteria, archaea, microalgae, and fungi. In some cases, these microbial associates comprise as much as 40% of the sponge volume and can contribute significantly to host metabolism (e.g., via photosynthesis or nitrogen fixation). We review in detail the diversity of microbes associated with sponges, including extensive 16S rRNA-based phylogenetic analyses which support the previously suggested existence of a sponge-specific microbiota. These analyses provide a suitable vantage point from which to consider the potential evolutionary and ecological ramifications of these widespread, sponge-specific microorganisms. Subsequently, we examine the ecology of sponge-microbe associations, including the establishment and maintenance of these sometimes intimate partnerships, the varied nature of the interactions (ranging from mutualism to host-pathogen relationships), and the broad-scale patterns of symbiont distribution. The ecological and evolutionary importance of sponge-microbe associations is mirrored by their enormous biotechnological potential: marine sponges are among the animal kingdom's most prolific producers of bioactive metabolites, and in at least some cases, the compounds are of microbial rather than sponge origin. We review the status of this important field, outlining the various approaches (e.g., cultivation, cell separation, and metagenomics) which have been employed to access the chemical wealth of sponge-microbe associations.

Sponge-Associated Microorganisms: Evolution, Ecology, and Biotechnological Potential

Little is known about the molecular mechanisms responsible for axis establishment during non-embryonic processes such as regeneration and homeostasis. To address this issue, we set out to analyze the role of the canonical Wnt pathway in planarians, flatworms renowned for their extraordinary morphological plasticity. Canonical Wnt signalling is an evolutionarily conserved mechanism to confer polarity during embryonic development, specifying the anteroposterior (AP) axis in most bilaterians and the dorsoventral (DV) axis in early vertebrate embryos. beta-Catenin is a key element in this pathway, although it is a bifunctional protein that is also involved in cell-cell adhesion. Here, we report the characterization of two beta-catenin homologs from Schmidtea mediterranea (Smed-betacatenin1/2). Loss of function of Smed-betacatenin1, but not Smed-betacatenin2, in both regenerating and intact planarians, generates radial-like hypercephalized planarians in which the AP axis disappears but the DV axis remains unaffected, representing a unique example of a striking body symmetry transformation. The radial-like hypercephalized phenotype demonstrates the requirement for Smed-betacatenin1 in AP axis re-establishment and maintenance, and supports a conserved role for canonical Wnt signalling in AP axis specification, whereas the role of beta-catenin in DV axis establishment would be a vertebrate innovation. When considered alongside the protein domains present in each S. mediterranea beta-catenin and the results of functional assays in Xenopus embryos demonstrating nuclear accumulation and axis induction with Smed-betacatenin1, but not Smed-betacatenin2, these data suggest that S. mediterranea beta-catenins could be functionally specialized and that only Smed-betacatenin1 is involved in Wnt signalling.

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Silencing of Smed-betacatenin1 generates radial-like hypercephalized planarians.

Planarians can regenerate a whole animal from only a small piece of their body, and have become an important model for stem cell biology. To identify regenerative processes dependent on Wnt growth factors in the planarian Schmidtea mediterranea ( Smed ), we analyzed RNAi phenotypes of Evi, a transmembrane protein specifically required for the secretion of Wnt ligands. We show that, during regeneration, Smed-evi loss-of-function prevents posterior identity, leading to two-headed planarians that resemble Smed -β -catenin1 RNAi animals. In addition, we observe regeneration defects of the nervous system that are not found after Smed -β -catenin1 RNAi. By systematic knockdown of all putative Smed Wnts in regenerating planarians, we identify Smed-WntP-1 and Smed-Wnt11-2 as the putative posterior organizers, and demonstrate that Smed-Wnt5 is a regulator of neuronal organization and growth. Thus, our study provides evidence that planarian Wnts are major regulators of regeneration, and that they signal through β-catenin-dependent and -independent pathways.

Smed-Evi/Wntless is required for β-catenin-dependent and -independent processes during planarian regeneration

Sponges were first grouped to the animal-plants or plant-animals then to the Zoophyta or Mesozoa and finally to the Parazoa. Only after the application of molecular biological techniques was it possible to place the Porifera monophyletically with the other metazoan phyla, justifying a unification of all multicellular animals to only one kingdom, the Metazoa. The first strong support came from the discovery that cell-cell and cell-matrix adhesion molecules that were cloned from sponges and were subsequently expressed share a high DNA sequence and protein function similarity with the corresponding molecules of other metazoans. Besides these evolutionary novelties for Metazoa, sponges also have morphogens and transcription factors in common with other metazoan phyla. Surprisingly, even those elements exist in Porifera, which are characteristic for pattern and axis formation. Recent studies showed that epithelial layers of sponges are sealed against the extracellular milieu through tight-junction proteins. The cell culture system from sponges, the primmorphs, was suitable for understanding morphogenetic events. Finally, stem cell marker genes were isolated, which underscored that sponge cells have the capacity to differentiate. In the relatively short period of time, approximately 200 million years, the basic pathways had to be established that allowed the transition for multicellular organisms to a colonial system through the formation of adhesion molecules; based on the development of a complex immune system and the apoptotic machinery of an integrated system, the Urmetazoa, which evolved approximately 800 million years ago, could be reached. Hence, the Bauplan of the hypothetical Urmetazoa can now be constructed according to genomic regulatory systems similar to those found in higher Metazoa. These data caused a paradigmatic change; the Porifera are complex and simple but by far not primitive.

Bauplan of urmetazoa: basis for genetic complexity of metazoa.

Planarians can undergo dramatic changes in body size and regenerate their entire body plan from small pieces after cutting This remarkable morphological plasticity has made them an excellent model in which to analyze phenomena such as morphogenesis, restoration of pattern and polarity, control of tissue proportions and tissue homeostasis They have a unique population of pluripotent stem cells in the adult that can give rise to all differentiated cell types, including the germ cells These cellular characteristics provide an excellent opportunity to study the mechanisms involved in the maintenance and differentiation of cell populations in intact and regenerating animals Until recently, the planarian model system lacked opportunities for genetic analysis; however, this handicap was overcome in the last decade through the development of new molecular methods which have been successfully applied to planarians These techniques have allowed analysis of the temporal and spatial expression of genes, as well as interference with gene function, generating the first phenotypes by loss or gain of function Finally, the sequencing of the planarian genome has provided the essential tools for an in-depth analysis of the genomic regulation of this model system In this review, we provide an overview of planarians as a model system for research into development and regeneration and describe new lines of investigation in this area

http://www.ijdb.ehu.es/web/descarga/paper/072414es

Planarian regeneration: achievements and future directions after 20 years of research.

Planarian regeneration was one of the first models in which the gradient concept was developed. Morphological studies based on the analysis of the regeneration rates of planarian fragments from different body regions, the generation of heteromorphoses, and experiments of tissue transplantation led T.H. Morgan (1901) and C.M Child (1911) to postulate different kinds of gradients responsible for the regenerative process in these highly plastic animals. However, after a century of research, the role of morphogens in planarian regeneration has yet to be demonstrated. This may change soon, as the sequencing of the planarian genome and the possibility of performing gene functional analysis by RNA interference (RNAi) have led to the isolation of elements of the bone morphogenetic protein (BMP), Wnt, and fibroblast growth factor (FGF) pathways that control patterning and axial polarity during planarian regeneration and homeostasis. Here, we discuss whether the actions of these molecules could be based on morphogenetic gradients.

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Teresa Adell

Papers

Silencing of Smed-betacatenin1 generates radial-like hypercephalized planarians.

Smed-Evi/Wntless is required for β-catenin-dependent and -independent processes during planarian regeneration

Bauplan of urmetazoa: basis for genetic complexity of metazoa.

Planarian regeneration: achievements and future directions after 20 years of research.

Gradients in planarian regeneration and homeostasis.