Vertebrates have greatly elaborated the basic chordate body plan and evolved highly distinctive genomes that have been sculpted by two whole-genome duplications. Here we sequence the genome of the Mediterranean amphioxus ( Branchiostoma lanceolatum ) and characterize DNA methylation, chromatin accessibility, histone modifications and transcriptomes across multiple developmental stages and adult tissues to investigate the evolution of the regulation of the chordate genome. Comparisons with vertebrates identify an intermediate stage in the evolution of differentially methylated enhancers, and a high conservation of gene expression and its cis -regulatory logic between amphioxus and vertebrates that occurs maximally at an earlier mid-embryonic phylotypic period. We analyse regulatory evolution after whole-genome duplications, and find that—in vertebrates—over 80% of broadly expressed gene families with multiple paralogues derived from whole-genome duplications have members that restricted their ancestral expression, and underwent specialization rather than subfunctionalization. Counter-intuitively, paralogues that restricted their expression increased the complexity of their regulatory landscapes. These data pave the way for a better understanding of the regulatory principles that underlie key vertebrate innovations.

Neural induction is the process through which pluripotent cells are committed to a neural fate. This first step of Central Nervous System formation is triggered by the "Spemann organizer" in amphibians and by homologous embryonic regions in other vertebrates. Studies in classical vertebrate models have produced contrasting views about the molecular nature of neural inducers and no unifying scheme could be drawn. Moreover, how this process evolved in the chordate lineage remains an unresolved issue. In this work, by using graft and micromanipulation experiments, we definitively establish that the dorsal blastopore lip of the cephalochordate amphioxus is homologous to the vertebrate organizer and is able to trigger the formation of neural tissues in a host embryo. In addition, we demonstrate that Nodal/Activin is the main signal eliciting neural induction in amphioxus, and that it also functions as a bona fide neural inducer in the classical vertebrate model Xenopus. Altogether, our results allow us to propose that Nodal/Activin was a major player of neural induction in the ancestor of chordates. This study further reveals the diversity of neural inducers deployed during chordate evolution and advocates against a universally conserved molecular explanation for this process.

Background: Since the course of breast cancer is often unpredictable, we wished to develop a model using characteristics of the primary tumour alone to predict prognosis. Methods: Several tumour features were determined, and after a median follow-up duration of 65 months, multivariate analysis identified tumour size and grade, oestrogen receptor concentration, axillary lymph node metastasis and tumour cell proliferation fraction (MIB-I count) as being independently associated with increases in risk for both relapse and death from breast cancer. A prognostic model was constructed using tumour size and grade, oestrogen receptor concentration and MIB-1 count only. A score of 1 for each was given to tumour size > 20 mm, tumour grade 2 or 3, oestrogen receptor concentration < 10 fmollmg cytosol protein and MIB-I count > 9%. Five groups established by assigning a combined score of 0, 1 , 2, 3 or 4 for each patient were analysed for their associations with disease-free and overall survivals. Results: This preliminary model predicted 5-year survival rates of 97, 91, 85, 68 and 50% for the five groups. The model was further simplified by excluding tumour grade from the analysis. The revised model identified four risk groups with predicted 5-year survival rates of 91, 86, 66 and 52%. This model, the Adelaide prognostic index, was also able to identify four risk groups in both node-negative and node-positive patients. Conclusions: The Adelaide prognostic index can be used to predict prognosis even in the absence of axillary lymph node information.

Neurons are a highly specialized cell type only found in metazoans. They can be scattered throughout the body or grouped together forming ganglia or nerve cords. During embryogenesis, centralized nervous systems develop from the ectoderm, which also forms the epidermis. How pluripotent ectodermal cells are directed towards neural or epidermal fates, and to which extent this process is shared among different animal lineages, are still open questions. Here, by using micromere explants, we were able to define in silico the putative Gene Regulatory Networks underlying the first steps of epidermis and central nervous system formation in the cephalochordate amphioxus. We propose that although the signal triggering neural induction in amphioxus (i.e. Nodal) is different from vertebrates, the main transcription factors implicated in this process are conserved. Moreover, our data reveal that transcription factors of the neural program seem to not only activate neural genes, but also to potentially have direct inputs into the epidermal Gene Regulatory Network, suggesting that Nodal signal might also contribute to neural fate commitment by repressing the epidermal program. Our functional data on whole embryos support this result and highlight the complex interactions among the transcription factors activated by the signalling pathways that drive ectodermal cell fate choice in chordates.

Forkhead box (Fox) genes code for transcription factors that play important roles in different biological processes. They are found in a wide variety of organisms and appeared in unicellular eukaryotes. In metazoans, the gene family includes many members that can be subdivided into 24 classes. Cephalochordates are key organisms to understand the functional evolution of gene families in the chordate lineage due to their phylogenetic position as an early divergent chordate, their simple anatomy and genome structure. In the genome of the cephalochordate amphioxus Branchiostoma floridae, 32 Fox genes were identified, with at least one member for each of the classes that were present in the ancestor of bilaterians. In this work we describe the expression pattern of 13 of these genes during the embryonic development of the Mediterranean amphioxus, Branchiostoma lanceolatum. We found that FoxK and FoxM genes present an ubiquitous expression while all the others show specific expression patterns restricted to diverse embryonic territories. Many of these expression patterns are conserved with vertebrates, suggesting that the main functions of Fox genes in chordates were present in their common ancestor.

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