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GTPases of the Rho family are molecular switches that play important roles in converting and amplifying external signals into cellular effects. Originally demonstrated to control the dynamics of the F-actin cytoskeleton, Rho GTPases have been implicated in many basic cellular processes that influence cell proliferation, differentiation, motility, adhesion, survival, or secretion. To elucidate the evolutionary history of the Rho family, we have analyzed over 20 species covering major eukaryotic clades from unicellular organisms to mammals, including platypus and opossum, and have reconstructed the ontogeny and the chronology of emergence of the different subfamilies. Our data establish that the 20 mammalian Rho members are structured into 8 subfamilies, among which Rac is the founder of the whole family. Rho, Cdc42, RhoUV, and RhoBTB subfamilies appeared before Coelomates and RhoJQ, Cdc42 isoforms, RhoDF, and Rnd emerged in chordates. In vertebrates, gene duplications and retrotranspositions increased the size of each chordate Rho subfamily, whereas RhoH, the last subfamily, arose probably by horizontal gene transfer. Rac1b, a Rac1 isoform generated by alternative splicing, emerged in amniotes, and RhoD, only in therians. Analysis of Rho mRNA expression patterns in mouse tissues shows that recent subfamilies have tissue-specific and low-level expression that supports their implication only in narrow time windows or in differentiated metabolic functions. These findings give a comprehensive view of the evolutionary canvas of the Rho family and provide guides for future structure and evolution studies of other components of Rho signaling pathways, in particular regulators of the RhoGEF family.

Mollusks are a major component of animal biodiversity and play a critical role in ecosystems and global food security. The Pacific oyster, Crassostrea (Magallana) gigas , is the most farmed bivalve mollusk in the world and is becoming a model species for invertebrate biology. Despite the extensive research on hemocytes, the immune cells of bivalves, their characterization remains elusive. Here, we were able to extensively characterize the diverse hemocytes and identified at least seven functionally distinct cell types and three hematopoietic lineages. A combination of single-cell RNA sequencing, quantitative cytology, cell sorting, functional assays, and pseudo-time analyses was used to deliver a comprehensive view of the distinct hemocyte types. This integrative analysis enabled us to reconcile molecular and cellular data and identify distinct cell types performing specialized immune functions, such as phagocytosis, reactive oxygen species production, copper accumulation, and expression of antimicrobial peptides. This study emphasized the need for more in depth studies of cellular immunity in mollusks and non-model invertebrates and set the ground for further comparative immunology studies at the cellular level. Pacific oysters are vital to the ecosystem. They are also a popular seafood and are increasingly used in life science research as a model to represent animals without a backbone (known as invertebrates). However, these oysters are prone to deadly infections caused by bacteria and viruses. Like humans, oysters and other invertebrates need an immune system to fight infections. Immune cells called hemocytes – which travel through the oyster’s body in a blood-like fluid called hemolymph – help eliminate bacteria, viruses and other disease-causing microbes by absorbing them, releasing toxic molecules, and producing natural antibiotics called antimicrobial peptides. However, it is still unclear how many types of hemocytes Pacific oysters have or what each type does. De La Forest Divonne et al. used single-cell RNA sequencing and other cell biology techniques to study the genetic activity and anatomy of immune cells in the Pacific oyster. The experiments confirmed that the oysters have at least seven distinct types of hemocytes, each with a specialized immune role, for example, some eat microbes while others produce antimicrobial peptides. The team also mapped how immature hemocytes develop into mature hemocytes with these specialist roles. This work provides the first detailed atlas of oyster immune cells and reveals how their immune system is organized and operates. A deeper understanding of oyster immune cells may guide the development of new strategies to reduce disease outbreaks in farmed or wild oysters. Before these benefits can be realized, future studies must test how each type of hemocyte responds to actual infections and explore whether targeted treatments or breeding programs can enhance the immune systems of farmed oysters.

The freshwater snail Biomphalaria glabrata is an intermediate host of Schistosoma mansoni , the agent of human intestinal schistosomiasis. However, much is to be discovered about its innate immune system that appears as a complex black box, in which the immune cells (called hemocytes) play a major role in both cellular and humoral response towards pathogens. Until now, hemocyte classification has been based exclusively on cell morphology and ultrastructural description and depending on the authors considered from 2 to 5 hemocyte populations have been described. In this study, we proposed to evaluate the hemocyte heterogeneity at the transcriptomic level. To accomplish this objective, we used single cell RNA sequencing (scRNAseq) technology coupled to a droplet-based system to separate hemocytes and analyze their transcriptome at a unique cell level in naive Biomphalaria glabrata snails. We were able to demonstrate the presence of 7 hemocyte transcriptomic populations defined by the expression of specific marker genes. As a result, scRNAseq approach showed a high heterogeneity within hemocytes, but provides a detailed description of the different hemocyte transcriptomic populations in B. glabrata supported by distinct cellular functions and lineage trajectory. As a main result, scRNAseq revealed the 3 main population as a super-group of hemocyte diversity but, on the contrary, a great hemocytes plasticity with a probable capacity of hemocytes to engage to different activation pathways. This work opens a new field of research to understand the role of hemocytes particularly in response to pathogens, and towards S. mansoni parasites.

Mollusks are a major component of animal biodiversity and play a critical role in ecosystems and global food security. The Pacific oyster, Crassostrea (Magallana) gigas , is the most farmed bivalve mollusk in the world and is becoming a model species for invertebrate biology. Despite the extensive research on hemocytes, the immune cells of bivalves, their characterization remains elusive. Here, we were able to extensively characterize the diverse hemocytes and identified at least seven functionally distinct cell types and three hematopoietic lineages. A combination of single-cell RNA sequencing, quantitative cytology, cell sorting, functional assays, and pseudo-time analyses was used to deliver a comprehensive view of the distinct hemocyte types. This integrative analysis enabled us to reconcile molecular and cellular data and identify distinct cell types performing specialized immune functions, such as phagocytosis, reactive oxygen species production, copper accumulation, and expression of antimicrobial peptides. This study emphasized the need for more in depth studies of cellular immunity in mollusks and non-model invertebrates and set the ground for further comparative immunology studies at the cellular level. Pacific oysters are vital to the ecosystem. They are also a popular seafood and are increasingly used in life science research as a model to represent animals without a backbone (known as invertebrates). However, these oysters are prone to deadly infections caused by bacteria and viruses. Like humans, oysters and other invertebrates need an immune system to fight infections. Immune cells called hemocytes – which travel through the oyster’s body in a blood-like fluid called hemolymph – help eliminate bacteria, viruses and other disease-causing microbes by absorbing them, releasing toxic molecules, and producing natural antibiotics called antimicrobial peptides. However, it is still unclear how many types of hemocytes Pacific oysters have or what each type does. De La Forest Divonne et al. used single-cell RNA sequencing and other cell biology techniques to study the genetic activity and anatomy of immune cells in the Pacific oyster. The experiments confirmed that the oysters have at least seven distinct types of hemocytes, each with a specialized immune role, for example, some eat microbes while others produce antimicrobial peptides. The team also mapped how immature hemocytes develop into mature hemocytes with these specialist roles. This work provides the first detailed atlas of oyster immune cells and reveals how their immune system is organized and operates. A deeper understanding of oyster immune cells may guide the development of new strategies to reduce disease outbreaks in farmed or wild oysters. Before these benefits can be realized, future studies must test how each type of hemocyte responds to actual infections and explore whether targeted treatments or breeding programs can enhance the immune systems of farmed oysters.

Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) has provided huge insight into the pathways, mechanisms and transcription factors that control differentiation. Here we use high-throughput RT–PCR technology to take a snapshot of splicing changes in the full spectrum of high- and low-expressed genes during induction of fibroblasts, from several donors, into iPSCs and their subsequent redifferentiation. We uncover a programme of concerted alternative splicing changes involved in late mesoderm differentiation and controlled by key splicing regulators MBNL1 and RBFOX2. These critical splicing adjustments arise early in vertebrate evolution and remain fixed in at least 10 genes (including PLOD2, CLSTN1, ATP2A1, PALM, ITGA6, KIF13A, FMNL3, PPIP5K1, MARK2 and FNIP1), implying that vertebrates require alternative splicing to fully implement the instructions of transcriptional control networks. MBNL and FOX splicing factors are known to have a role in the differentiation of muscle and the nervous system during development. In this study, the authors show that MBNL1 and RBFOX2 regulate alternative splicing of genes that are required specifically for late mesoderm differentiation.

Mollusks are a major component of animal biodiversity and play a critical role in ecosystems and global food security. The Pacific oyster, Crassostrea (Magallana) gigas, is the most farmed bivalve mollusk in the world and is becoming a model species for invertebrate biology. Despite the extensive research on hemocytes, the immune cells of bivalves, their characterization remains elusive. Here we were able to extensively characterize the diverse hemocytes and identified at least seven functionally distinct cell types and three hematopoietic lineages. A combination of single-cell RNA sequencing, quantitative cytology, cell sorting, functional assays and pseudo-time analyses was used to deliver a comprehensive view of the distinct hemocyte types. This integrative analysis enabled us to reconcile molecular and cellular data and identify distinct cell types performing specialized immune functions, such as phagocytosis, reactive oxygen species production, copper accumulation, and expression of antimicrobial peptides. This study emphasized the need for more in depth studies of cellular immunity in mollusks and non-model invertebrates and set the ground for further comparative immunology studies at the cellular level.

Alternative splicing allows organisms to rapidly modulate protein functions to physiological changes and therefore represents a highly versatile adaptive process. We investigated the conservation of the evolutionary history of the “Fox” family of RNA-binding splicing factors (RBFOX) as well as the conservation of regulated alternative splicing of the genes they control. We found that the RBFOX proteins are conserved in all metazoans examined. In humans, Fox proteins control muscle-specific alternative splicing of many genes but despite the conservation of splicing factors, conservation of regulation of alternative splicing has never been demonstrated between man and nonvertebrate species. Therefore, we studied 40 known Fox-regulated human exons and found that 22 had a tissue-specific splicing pattern in muscle and heart. Of these, 11 were spliced in the same tissue-specific manner in mouse tissues and 4 were tissue-specifically spliced in muscle and heart of the frog Xenopus laevis. The inclusion of two of these alternative exons was also downregulated during tadpole development. Of the 40 in the starting set, the most conserved alternative splicing event was in the transforming growth factor (TGF) beta-activated kinase Tak1 (MAP3K7) as this was also muscle specific in urochordates and in Ambulacraria, the most ancient deuterostome clade. We found exclusion of the muscle-specific exon of Tak1 was itself under control of TGF beta in cell culture and consistently that TGF beta caused an upregulation of Fox2 (RBFOX2) expression. The alternative exon, which codes for an in-frame 27 amino acids between the kinase and known regulatory domain of TAK1, contains conserved features in all organisms including potential phosphorylation sites and likely has an important conserved function in TGF beta signaling and development. This study establishes that deuterostomes share a remarkable conserved physiological process that involves a splicing factor and expression of tissue-specific isoforms of a target gene that expedites a highly conserved signaling pathway.

Since the mid 1970s, cancer has been described as a process of Darwinian evolution, with somatic cellular selection and evolution being the fundamental processes leading to malignancy and its many manifestations (neoangiogenesis, evasion of the immune system, metastasis, and resistance to therapies). Historically, little attention has been placed on applications of evolutionary biology to understanding and controlling neoplastic progression and to prevent therapeutic failures. This is now beginning to change, and there is a growing international interest in the interface between cancer and evolutionary biology. The objective of this introduction is first to describe the basic ideas and concepts linking evolutionary biology to cancer. We then present four major fronts where the evolutionary perspective is most developed, namely laboratory and clinical models, mathematical models, databases, and techniques and assays. Finally, we discuss several of the most promising challenges and future prospects in this interdisciplinary research direction in the war against cancer.

Mollusks are a major component of animal biodiversity and play a critical role in ecosystems and global food security. The Pacific oyster, Crassostrea (Magallana) gigas, is the most farmed bivalve mollusk in the world and is becoming a model species for invertebrate biology. Despite the extensive research on hemocytes, the immune cells of bivalves, their characterization remains elusive. Here we were able to extensively characterize the diverse hemocytes and identified at least seven functionally distinct cell types and three hematopoietic lineages. A combination of single-cell RNA sequencing, quantitative cytology, cell sorting, functional assays and pseudo-time analyses was used to deliver a comprehensive view of the distinct hemocyte types. This integrative analysis enabled us to reconcile molecular and cellular data and identify distinct cell types performing specialized immune functions, such as phagocytosis, reactive oxygen species production, copper accumulation, and expression of antimicrobial peptides. This study emphasized the need for more in depth studies of cellular immunity in mollusks and non-model invertebrates and set the ground for further comparative immunology studies at the cellular level.Competing Interest StatementThe authors have declared no competing interest.Footnotes* Revision of the paper to improve the readability of the figures, enrich the introduction, and the discussion.

Transmissible cancer cell lines are rare biological entities giving rise to diseases at the crossroads of cancer and parasitic diseases. These malignant cells have acquired the amazing capacity to spread from host to host. They have been described only in dogs, Tasmanian devils and marine bivalves. The Mytilus trossulus Bivalve Transmissible Neoplasia 2 (MtrBTN2) lineage has even acquired the capacity to spread inter-specifically between marine mussels of the Mytilus edulis complex worldwide. To identify the oncogenic processes underpinning the biology of these atypical cancers we performed transcriptomics of MtrBTN2 cells. Differential gene expression, enrichment, protein-protein interaction network, and targeted analyses were used. Overall, our results suggests that the long-term evolution of MtrBTN2 has led to the accumulation of multiple cancerous traits. We also highlight that vertebrate and lophotrochozoan cancers share a large panel of common drivers, which supports the hypothesis of an ancient origin of oncogenic processes in bilaterians.Competing Interest StatementThe authors have declared no competing interest.