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1.
Brief Bioinform ; 25(4)2024 May 23.
Article in English | MEDLINE | ID: mdl-38980372

ABSTRACT

Around 50 years ago, molecular biology opened the path to understand changes in forms, adaptations, complexity, or the basis of human diseases through myriads of reports on gene birth, gene duplication, gene expression regulation, and splicing regulation, among other relevant mechanisms behind gene function. Here, with the advent of big data and artificial intelligence (AI), we focus on an elusive and intriguing mechanism of gene function regulation, RNA editing, in which a single nucleotide from an RNA molecule is changed, with a remarkable impact in the increase of the complexity of the transcriptome and proteome. We present a new generation approach to assess the functional conservation of the RNA-editing targeting mechanism using two AI learning algorithms, random forest (RF) and bidirectional long short-term memory (biLSTM) neural networks with an attention layer. These algorithms, combined with RNA-editing data coming from databases and variant calling from same-individual RNA and DNA-seq experiments from different species, allowed us to predict RNA-editing events using both primary sequence and secondary structure. Then, we devised a method for assessing conservation or divergence in the molecular mechanisms of editing completely in silico: the cross-testing analysis. This novel method not only helps to understand the conservation of the editing mechanism through evolution but could set the basis for achieving a better understanding of the adenosine-targeting mechanism in other fields.


Subject(s)
Machine Learning , RNA Editing , Humans , Algorithms , Computer Simulation , Computational Biology/methods , Neural Networks, Computer , RNA/genetics , RNA/metabolism
2.
Redox Biol ; 66: 102862, 2023 10.
Article in English | MEDLINE | ID: mdl-37660443

ABSTRACT

The retina is particularly vulnerable to genetic and environmental alterations that generate oxidative stress and cause cellular damage in photoreceptors and other retinal neurons, eventually leading to cell death. CERKL (CERamide Kinase-Like) mutations cause Retinitis Pigmentosa and Cone-Rod Dystrophy in humans, two disorders characterized by photoreceptor degeneration and progressive vision loss. CERKL is a resilience gene against oxidative stress, and its overexpression protects cells from oxidative stress-induced apoptosis. Besides, CERKL contributes to stress granule-formation and regulates mitochondrial dynamics in the retina. Using the CerklKD/KO albino mouse model, which recapitulates the human disease, we aimed to study the impact of Cerkl knockdown on stress response and activation of photoreceptor death mechanisms upon light/oxidative stress. After acute light injury, we assessed immediate or late retinal stress response, by combining both omic and non-omic approaches. Our results show that Cerkl knockdown increases ROS levels and causes a basal exacerbated stress state in the retina, through alterations in glutathione metabolism and stress granule production, overall compromising an adequate response to additional oxidative damage. As a consequence, several cell death mechanisms are triggered in CerklKD/KO retinas after acute light stress. Our studies indicate that Cerkl gene is a pivotal player in regulating light-challenged retinal homeostasis and shed light on how mutations in CERKL lead to blindness by dysregulation of the basal oxidative stress response in the retina.


Subject(s)
Phosphotransferases (Alcohol Group Acceptor) , Retinal Degeneration , Retinitis Pigmentosa , Animals , Humans , Mice , Disease Models, Animal , Homeostasis , Oxidative Stress , Retina , Retinal Degeneration/genetics , Retinitis Pigmentosa/genetics , Phosphotransferases (Alcohol Group Acceptor)/genetics
3.
Mol Psychiatry ; 27(9): 3739-3748, 2022 09.
Article in English | MEDLINE | ID: mdl-35501409

ABSTRACT

Genetic variants in YWHAZ contribute to psychiatric disorders such as autism spectrum disorder and schizophrenia, and have been related to an impaired neurodevelopment in humans and mice. Here, we have used zebrafish to investigate the mechanisms by which YWHAZ contributes to neurodevelopmental disorders. We observed that ywhaz expression was pan-neuronal during developmental stages and restricted to Purkinje cells in the adult cerebellum, cells that are described to be reduced in number and size in autistic patients. We then performed whole-brain imaging in wild-type and ywhaz CRISPR/Cas9 knockout (KO) larvae and found altered neuronal activity and connectivity in the hindbrain. Adult ywhaz KO fish display decreased levels of monoamines in the hindbrain and freeze when exposed to novel stimuli, a phenotype that can be reversed with drugs that target monoamine neurotransmission. These findings suggest an important role for ywhaz in establishing neuronal connectivity during development and modulating both neurotransmission and behaviour in adults.


Subject(s)
14-3-3 Proteins , Brain , Zebrafish Proteins , Zebrafish , Animals , Humans , 14-3-3 Proteins/genetics , Autism Spectrum Disorder/genetics , Autism Spectrum Disorder/physiopathology , Autistic Disorder/genetics , Autistic Disorder/physiopathology , Brain/metabolism , Brain/physiopathology , Neurodevelopmental Disorders/genetics , Neurodevelopmental Disorders/physiopathology , Zebrafish/genetics , Zebrafish Proteins/genetics
4.
Front Cell Dev Biol ; 9: 749806, 2021.
Article in English | MEDLINE | ID: mdl-34778260

ABSTRACT

c-Jun N-terminal kinase (JNK) is a multi-functional protein involved in a diverse array of context-dependent processes, including apoptosis, cell cycle regulation, adhesion, and differentiation. It is integral to several signalling cascades, notably downstream of non-canonical Wnt and mitogen activated protein kinase (MAPK) signalling pathways. As such, it is a key regulator of cellular behaviour and patterning during embryonic development across the animal kingdom. The cephalochordate amphioxus is an invertebrate chordate model system straddling the invertebrate to vertebrate transition and is thus ideally suited for comparative studies of morphogenesis. However, next to nothing is known about JNK signalling or cellular processes in this lineage. Pharmacological inhibition of JNK signalling using SP600125 during embryonic development arrests gastrula invagination and causes convergence extension-like defects in axial elongation, particularly of the notochord. Pharynx formation and anterior oral mesoderm derivatives like the preoral pit are also affected. This is accompanied by tissue-specific transcriptional changes, including reduced expression of six3/6 and wnt2 in the notochord, and ectopic wnt11 in neurulating embryos treated at late gastrula stages. Cellular delamination results in accumulation of cells in the gut cavity and a dorsal fin-like protrusion, followed by secondary Caspase-3-mediated apoptosis of polarity-deficient cells, a phenotype only partly rescued by co-culture with the pan-Caspase inhibitor Z-VAD-fmk. Ectopic activation of extracellular signal regulated kinase (ERK) signalling in the neighbours of extruded notochord and neural cells, possibly due to altered adhesive and tensile properties, as well as defects in cellular migration, may explain some phenotypes caused by JNK inhibition. Overall, this study supports conserved functions of JNK signalling in mediating the complex balance between cell survival, apoptosis, differentiation, and cell fate specification during cephalochordate morphogenesis.

5.
Nature ; 599(7885): 431-435, 2021 11.
Article in English | MEDLINE | ID: mdl-34789899

ABSTRACT

A central question in chordate evolution is the origin of sessility in adult ascidians, and whether the appendicularian complete free-living style represents a primitive or derived condition among tunicates1. According to the 'a new heart for a new head' hypothesis, the evolution of the cardiopharyngeal gene regulatory network appears as a pivotal aspect to understand the evolution of the lifestyles of chordates2-4. Here we show that appendicularians experienced massive ancestral losses of cardiopharyngeal genes and subfunctions, leading to the 'deconstruction' of two ancestral modules of the tunicate cardiopharyngeal gene regulatory network. In ascidians, these modules are related to early and late multipotency, which is involved in lineage cell-fate determination towards the first and second heart fields and siphon muscles. Our work shows that the deconstruction of the cardiopharyngeal gene regulatory network involved the regressive loss of the siphon muscle, supporting an evolutionary scenario in which ancestral tunicates had a sessile ascidian-like adult lifestyle. In agreement with this scenario, our findings also suggest that this deconstruction contributed to the acceleration of cardiogenesis and the redesign of the heart into an open-wide laminar structure in appendicularians as evolutionary adaptations during their transition to a complete pelagic free-living style upon the innovation of the food-filtering house5.


Subject(s)
Biological Evolution , Heart/anatomy & histology , Heart/growth & development , Urochordata/anatomy & histology , Urochordata/physiology , Animals , Cell Lineage , Gene Regulatory Networks , Locomotion , Myocardium/cytology , Myocardium/metabolism , Urochordata/cytology , Urochordata/genetics
6.
Front Cell Dev Biol ; 9: 713918, 2021.
Article in English | MEDLINE | ID: mdl-34295903

ABSTRACT

Which is the origin of genes is a fundamental question in Biology, indeed a question older than the discovery of genes itself. For more than a century, it was uneven to think in origins other than duplication and divergence from a previous gene. In recent years, however, the intersection of genetics, embryonic development, and bioinformatics, has brought to light that de novo generation from non-genic DNA, horizontal gene transfer and, noticeably, virus and transposon invasions, have shaped current genomes, by integrating those newcomers into old gene networks, helping to shape morphological and physiological innovations. We here summarized some of the recent research in the field, mostly in the vertebrate lineage with a focus on protein-coding novelties, showing that the placenta, the adaptative immune system, or the highly developed neocortex, among other innovations, are linked to de novo gene creation or domestication of virus and transposons. We provocatively suggest that the high tolerance to virus infections by bats may also be related to previous virus and transposon invasions in the bat lineage.

7.
Neurobiol Dis ; 156: 105405, 2021 08.
Article in English | MEDLINE | ID: mdl-34048907

ABSTRACT

The retina is a highly active metabolic organ that displays a particular vulnerability to genetic and environmental factors causing stress and homeostatic imbalance. Mitochondria constitute a bioenergetic hub that coordinates stress response and cellular homeostasis, therefore structural and functional regulation of the mitochondrial dynamic network is essential for the mammalian retina. CERKL (ceramide kinase like) is a retinal degeneration gene whose mutations cause Retinitis Pigmentosa in humans, a visual disorder characterized by photoreceptors neurodegeneration and progressive vision loss. CERKL produces multiple isoforms with a dynamic subcellular localization. Here we show that a pool of CERKL isoforms localizes at mitochondria in mouse retinal ganglion cells. The depletion of CERKL levels in CerklKD/KO(knockdown/knockout) mouse retinas cause increase of autophagy, mitochondrial fragmentation, alteration of mitochondrial distribution, and dysfunction of mitochondrial-dependent bioenergetics and metabolism. Our results support CERKL as a regulator of autophagy and mitochondrial biology in the mammalian retina.


Subject(s)
Mitochondria/metabolism , Phosphotransferases (Alcohol Group Acceptor)/deficiency , Retina/metabolism , Retinal Dystrophies/metabolism , Retinal Ganglion Cells/metabolism , Animals , Autophagy/physiology , Cells, Cultured , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Mitochondria/genetics , Mitochondria/ultrastructure , Phosphotransferases (Alcohol Group Acceptor)/genetics , Retina/ultrastructure , Retinal Dystrophies/genetics , Retinal Dystrophies/pathology , Retinal Ganglion Cells/ultrastructure , Retinitis Pigmentosa/genetics , Retinitis Pigmentosa/metabolism , Retinitis Pigmentosa/pathology
8.
Sci Rep ; 11(1): 2947, 2021 02 03.
Article in English | MEDLINE | ID: mdl-33536473

ABSTRACT

The forkhead box (Fox) genes encode transcription factors that control several key aspects of development. Present in the ancestor of all eukaryotes, Fox genes underwent several duplications followed by loss and diversification events that gave rise to the current 25 families. However, few Fox members have been identified from the Lophotrochozoa clade, and specifically from planarians, which are a unique model for understanding development, due to the striking plasticity of the adult. The aim of this study was to identify and perform evolutionary and functional studies of the Fox genes of lophotrochozoan species and, specifically, of the planarian Schmidtea mediterranea. Generating a pipeline for identifying Forkhead domains and using phylogenetics allowed us the phylogenetic reconstruction of Fox genes. We corrected the annotation for misannotated genes and uncovered a new family, the QD, present in all metazoans. According to the new phylogeny, the 27 Fox genes found in Schmidtea mediterranea were classified into 12 families. In Platyhelminthes, family losses were accompanied by extensive gene diversification and the appearance of specific families, the A(P) and N(P). Among the newly identified planarian Fox genes, we found a single copy of foxO, which shows an evolutionary conserved role in controlling cell death.


Subject(s)
Biological Evolution , Forkhead Transcription Factors/metabolism , Helminth Proteins/metabolism , Planarians/genetics , Regulated Cell Death/genetics , Animals , Gene Expression Profiling , Gene Expression Regulation , Phylogeny
9.
Genes (Basel) ; 11(12)2020 11 30.
Article in English | MEDLINE | ID: mdl-33265998

ABSTRACT

RNA editing is a relatively unexplored process in which transcribed RNA is modified at specific nucleotides before translation, adding another level of regulation of gene expression. Cephalopods use it extensively to increase the regulatory complexity of their nervous systems, and mammals use it too, but less prominently. Nevertheless, little is known about the specifics of RNA editing in most of the other clades and the relevance of RNA editing from an evolutionary perspective remains unknown. Here we analyze a key element of the editing machinery, the ADAR (adenosine deaminase acting on RNA) gene family, in an animal with a key phylogenetic position at the root of chordates: the cephalochordate amphioxus. We show, that as in cephalopods, ADAR genes in amphioxus are predominantly expressed in the nervous system; we identify a number of RNA editing events in amphioxus; and we provide a newly developed method to identify RNA editing events in highly polymorphic genomes using orthology as a guide. Overall, our work lays the foundations for future comparative analysis of RNA-editing events across the metazoan tree.


Subject(s)
Adenosine Deaminase/genetics , RNA Editing/genetics , RNA-Binding Proteins/genetics , RNA/genetics , Animals , Cephalopoda/genetics , Evolution, Molecular , Gene Expression/genetics , Humans , Nervous System/metabolism , Phylogeny
10.
Genome Biol ; 21(1): 267, 2020 10 26.
Article in English | MEDLINE | ID: mdl-33100228

ABSTRACT

BACKGROUND: One of the most unusual sources of phylogenetically restricted genes is the molecular domestication of transposable elements into a host genome as functional genes. Although these kinds of events are sometimes at the core of key macroevolutionary changes, their origin and organismal function are generally poorly understood. RESULTS: Here, we identify several previously unreported transposable element domestication events in the human and mouse genomes. Among them, we find a remarkable molecular domestication that gave rise to a multigenic family in placental mammals, the Bex/Tceal gene cluster. These genes, which act as hub proteins within diverse signaling pathways, have been associated with neurological features of human patients carrying genomic microdeletions in chromosome X. The Bex/Tceal genes display neural-enriched patterns and are differentially expressed in human neurological disorders, such as autism and schizophrenia. Two different murine alleles of the cluster member Bex3 display morphological and physiopathological brain modifications, such as reduced interneuron number and hippocampal electrophysiological imbalance, alterations that translate into distinct behavioral phenotypes. CONCLUSIONS: We provide an in-depth understanding of the emergence of a gene cluster that originated by transposon domestication and gene duplication at the origin of placental mammals, an evolutionary process that transformed a non-functional transposon sequence into novel components of the eutherian genome. These genes were integrated into existing signaling pathways involved in the development, maintenance, and function of the CNS in eutherians. At least one of its members, Bex3, is relevant for higher brain functions in placental mammals and may be involved in human neurological disorders.


Subject(s)
Apoptosis Regulatory Proteins/genetics , DNA Transposable Elements , Domestication , Eutheria/genetics , Multigene Family , Animals , Autism Spectrum Disorder/genetics , Brain , CRISPR-Cas Systems , DNA-Binding Proteins/genetics , Evolution, Molecular , Female , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Nerve Tissue Proteins/genetics , Neurodevelopmental Disorders/genetics , Nuclear Proteins/genetics , Phylogeny , Placenta , Pregnancy , TOR Serine-Threonine Kinases/genetics , Transcription Factors/genetics
11.
BMC Biol ; 18(1): 68, 2020 06 16.
Article in English | MEDLINE | ID: mdl-32546156

ABSTRACT

BACKGROUND: The homeobox genes Pdx and Cdx are widespread across the animal kingdom and part of the small ParaHox gene cluster. Gene expression patterns suggest ancient roles for Pdx and Cdx in patterning the through-gut of bilaterian animals although functional data are available for few lineages. To examine evolutionary conservation of Pdx and Cdx gene functions, we focus on amphioxus, small marine animals that occupy a pivotal position in chordate evolution and in which ParaHox gene clustering was first reported. RESULTS: Using transcription activator-like effector nucleases (TALENs), we engineer frameshift mutations in the Pdx and Cdx genes of the amphioxus Branchiostoma floridae and establish mutant lines. Homozygous Pdx mutants have a defect in amphioxus endoderm, manifest as loss of a midgut region expressing endogenous GFP. The anus fails to open in homozygous Cdx mutants, which also have defects in posterior body extension and epidermal tail fin development. Treatment with an inverse agonist of retinoic acid (RA) signalling partially rescues the axial and tail fin phenotypes indicating they are caused by increased RA signalling. Gene expression analyses and luciferase assays suggest that posterior RA levels are kept low in wild type animals by a likely direct transcriptional regulation of a Cyp26 gene by Cdx. Transcriptome analysis reveals extensive gene expression changes in mutants, with a disproportionate effect of Pdx and Cdx on gut-enriched genes and a colinear-like effect of Cdx on Hox genes. CONCLUSIONS: These data reveal that amphioxus Pdx and Cdx have roles in specifying middle and posterior cell fates in the endoderm of the gut, roles that likely date to the origin of Bilateria. This conclusion is consistent with these two ParaHox genes playing a role in the origin of the bilaterian through-gut with a distinct anus, morphological innovations that contributed to ecological change in the Cambrian. In addition, we find that amphioxus Cdx promotes body axis extension through a molecular mechanism conserved with vertebrates. The axial extension role for Cdx dates back at least to the origin of Chordata and may have facilitated the evolution of the post-anal tail and active locomotion in chordates.


Subject(s)
Anal Canal/embryology , Gastrointestinal Tract/embryology , Homeodomain Proteins/genetics , Lancelets/embryology , Mutation , Tail/embryology , Transcription Factors/genetics , Animals , Embryo, Nonmammalian , Embryonic Development/genetics , Genes, Homeobox , Homeodomain Proteins/metabolism , Lancelets/genetics , Transcription Factors/metabolism
12.
Development ; 147(7)2020 04 08.
Article in English | MEDLINE | ID: mdl-32122990

ABSTRACT

Control of cell number is crucial to define body size during animal development and to restrict tumoral transformation. The cell number is determined by the balance between cell proliferation and cell death. Although many genes are known to regulate those processes, the molecular mechanisms underlying the relationship between cell number and body size remain poorly understood. This relationship can be better understood by studying planarians, flatworms that continuously change their body size according to nutrient availability. We identified a novel gene family, blitzschnell (bls), that consists of de novo and taxonomically restricted genes that control cell proliferation:cell death ratio. Their silencing promotes faster regeneration and increases cell number during homeostasis. Importantly, this increase in cell number leads to an increase in body size only in a nutrient-rich environment; in starved planarians, silencing results in a decrease in cell size and cell accumulation that ultimately produces overgrowths. bls expression is downregulated after feeding and is related to activity of the insulin/Akt/mTOR network, suggesting that the bls family evolved in planarians as an additional mechanism for restricting cell number in nutrient-fluctuating environments.


Subject(s)
Apoptosis Regulatory Proteins/physiology , Cell Death/genetics , Cell Proliferation/genetics , Multigene Family/physiology , Planarians , Animals , Animals, Genetically Modified , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Cell Count , Chromosome Mapping , Gene Expression Regulation, Developmental , Homeostasis/genetics , Planarians/classification , Planarians/cytology , Planarians/genetics , Planarians/physiology , Regeneration/genetics , Tandem Repeat Sequences
13.
Semin Cell Dev Biol ; 102: 40-47, 2020 06.
Article in English | MEDLINE | ID: mdl-31761444

ABSTRACT

The cerebrospinal fluid (CSF) is a waterly, colorless fluid contained within the brain ventricles and the cranial and spinal subarachnoid spaces. CSF physiological functions range from hydromechanical protection of the central nervous system (CNS) to CNS modulation of developmental processes and regulation of interstitial fluid homeostasis. Optic nerve (ON) is surrounded by CSF circulating in the subarachnoid spaces and is exposed to both CSF (CSFP) and intra ocular (IOP) pressures, which converge at the lamina cribrosa (LC) as two opposite forces. The trans-lamina cribrosa pressure gradient (TLPG) is defined as IOP - CSFP and its alterations (due either to an elevation in IOP or a reduction in ICP) could result in structural damaging of the ON, including glaucomatous changes. The purpose of this review is to update the readers on the CSF contribution in controlling the functions/dysfunctions of ON by regulating homeostasis at LC. We also highlight emerging parallelisms regarding the expression of cilia-related genes in the regulation of common functions of body fluids in both brain and eye structures.


Subject(s)
Cerebrospinal Fluid/metabolism , Eye/metabolism , Homeostasis , Pressure , Cerebrospinal Fluid Pressure , Humans
14.
Biology (Basel) ; 8(3)2019 Aug 24.
Article in English | MEDLINE | ID: mdl-31450588

ABSTRACT

Homologous long non-coding RNAs (lncRNAs) are elusive to identify by sequence similarity due to their fast-evolutionary rate. Here we develop LincOFinder, a pipeline that finds conserved intergenic lncRNAs (lincRNAs) between distant related species by means of microsynteny analyses. Using this tool, we have identified 16 bona fide homologous lincRNAs between the amphioxus and human genomes. We characterized and compared in amphioxus and Xenopus the expression domain of one of them, Hotairm1, located in the anterior part of the Hox cluster. In addition, we analyzed the function of this lincRNA in Xenopus, showing that its disruption produces a severe headless phenotype, most probably by interfering with the regulation of the Hox cluster. Our results strongly suggest that this lincRNA has probably been regulating the Hox cluster since the early origin of chordates. Our work pioneers the use of syntenic searches to identify non-coding genes over long evolutionary distances and helps to further understand lncRNA evolution.

15.
Elife ; 72018 11 22.
Article in English | MEDLINE | ID: mdl-30465522

ABSTRACT

Glutamate receptors are divided in two unrelated families: ionotropic (iGluR), driving synaptic transmission, and metabotropic (mGluR), which modulate synaptic strength. The present classification of GluRs is based on vertebrate proteins and has remained unchanged for over two decades. Here we report an exhaustive phylogenetic study of GluRs in metazoans. Importantly, we demonstrate that GluRs have followed different evolutionary histories in separated animal lineages. Our analysis reveals that the present organization of iGluRs into six classes does not capture the full complexity of their evolution. Instead, we propose an organization into four subfamilies and ten classes, four of which have never been previously described. Furthermore, we report a sister class to mGluR classes I-III, class IV. We show that many unreported proteins are expressed in the nervous system, and that new Epsilon receptors form functional ligand-gated ion channels. We propose an updated classification of glutamate receptors that includes our findings.


Subject(s)
Evolution, Molecular , Genetic Variation , Receptors, Ionotropic Glutamate/genetics , Receptors, Metabotropic Glutamate/genetics , Amino Acid Sequence , Animals , Bayes Theorem , Binding Sites/genetics , HEK293 Cells , Humans , Models, Molecular , Phylogeny , Protein Domains , Receptors, Ionotropic Glutamate/chemistry , Receptors, Ionotropic Glutamate/classification , Receptors, Metabotropic Glutamate/chemistry , Receptors, Metabotropic Glutamate/classification , Sequence Homology, Amino Acid
16.
Front Immunol ; 9: 2525, 2018.
Article in English | MEDLINE | ID: mdl-30450099

ABSTRACT

Toll-like receptors (TLRs) are important for raising innate immune responses in both invertebrates and vertebrates. Amphioxus belongs to an ancient chordate lineage which shares key features with vertebrates. The genomic research on TLR genes in Branchiostoma floridae and Branchiostoma belcheri reveals the expansion of TLRs in amphioxus. However, the repertoire of TLRs in Branchiostoma lanceolatum has not been studied and the functionality of amphioxus TLRs has not been reported. We have identified from transcriptomic data 30 new putative TLRs in B. lanceolatum and all of them are transcribed in adult amphioxus. Phylogenetic analysis showed that the repertoire of TLRs consists of both non-vertebrate and vertebrate-like TLRs. It also indicated a lineage-specific expansion in orthologous clusters of the vertebrate TLR11 family. We did not detect any representatives of the vertebrate TLR1, TLR3, TLR4, TLR5 and TLR7 families. To gain insight into these TLRs, we studied in depth a particular TLR highly similar to a B. belcheri gene annotated as bbtTLR1. The phylogenetic analysis of this novel BlTLR showed that it clusters with the vertebrate TLR11 family and it might be more related to TLR13 subfamily according to similar domain architecture. Transient and stable expression in HEK293 cells showed that the BlTLR localizes on the plasma membrane, but it did not respond to the most common mammalian TLR ligands. However, when the ectodomain of BlTLR is fused to the TIR domain of human TLR2, the chimeric protein could indeed induce NF-κB transactivation in response to the viral ligand Poly I:C, also indicating that in amphioxus, specific accessory proteins are needed for downstream activation. Based on the phylogenetic, subcellular localization and functional analysis, we propose that the novel BlTLR might be classified as an antiviral receptor sharing at least partly the functions performed by vertebrate TLR22. TLR22 is thought to be viral teleost-specific TLR but here we demonstrate that teleosts and amphioxus TLR22-like probably shared a common ancestor. Additional functional studies with other lancelet TLR genes will enrich our understanding of the immune response in amphioxus and will provide a unique perspective on the evolution of the immune system.


Subject(s)
Lancelets/genetics , RNA, Double-Stranded/genetics , Toll-Like Receptors/genetics , Animals , Cell Line , Cell Membrane/genetics , Genome/genetics , Genomics/methods , HEK293 Cells , Humans , Immunity, Innate/genetics , Mammals/genetics , NF-kappa B/genetics , Phylogeny , Sequence Analysis, DNA/methods , Species Specificity , Transcriptional Activation/genetics , Transcriptome/genetics
17.
Nat Commun ; 8(1): 1799, 2017 11 27.
Article in English | MEDLINE | ID: mdl-29180615

ABSTRACT

Epithelial-mesenchymal interactions are crucial for the development of numerous animal structures. Thus, unraveling how molecular tools are recruited in different lineages to control interplays between these tissues is key to understanding morphogenetic evolution. Here, we study Esrp genes, which regulate extensive splicing programs and are essential for mammalian organogenesis. We find that Esrp homologs have been independently recruited for the development of multiple structures across deuterostomes. Although Esrp is involved in a wide variety of ontogenetic processes, our results suggest ancient roles in non-neural ectoderm and regulating specific mesenchymal-to-epithelial transitions in deuterostome ancestors. However, consistent with the extensive rewiring of Esrp-dependent splicing programs between phyla, most developmental defects observed in vertebrate mutants are related to other types of morphogenetic processes. This is likely connected to the origin of an event in Fgfr, which was recruited as an Esrp target in stem chordates and subsequently co-opted into the development of many novel traits in vertebrates.


Subject(s)
Embryonic Development/genetics , Epithelial-Mesenchymal Transition/physiology , RNA Splicing/physiology , RNA-Binding Proteins/physiology , Animals , Biological Evolution , CRISPR-Cas Systems , Exons/physiology , Female , Gene Expression Regulation, Developmental/physiology , Gene Knockdown Techniques , Lancelets , Male , Mutation , RNA-Binding Proteins/genetics , Sequence Homology, Amino Acid , Signal Transduction/genetics , Strongylocentrotus purpuratus , Urochordata , Zebrafish
18.
PLoS Biol ; 15(4): e2001573, 2017 04.
Article in English | MEDLINE | ID: mdl-28422959

ABSTRACT

All vertebrate brains develop following a common Bauplan defined by anteroposterior (AP) and dorsoventral (DV) subdivisions, characterized by largely conserved differential expression of gene markers. However, it is still unclear how this Bauplan originated during evolution. We studied the relative expression of 48 genes with key roles in vertebrate neural patterning in a representative amphioxus embryonic stage. Unlike nonchordates, amphioxus develops its central nervous system (CNS) from a neural plate that is homologous to that of vertebrates, allowing direct topological comparisons. The resulting genoarchitectonic model revealed that the amphioxus incipient neural tube is unexpectedly complex, consisting of several AP and DV molecular partitions. Strikingly, comparison with vertebrates indicates that the vertebrate thalamus, pretectum, and midbrain domains jointly correspond to a single amphioxus region, which we termed Di-Mesencephalic primordium (DiMes). This suggests that these domains have a common developmental and evolutionary origin, as supported by functional experiments manipulating secondary organizers in zebrafish and mice.


Subject(s)
Brain/embryology , Embryo, Nonmammalian/embryology , Lancelets/embryology , Neural Tube/embryology , Vertebrates/embryology , Animals , Biological Evolution , Body Patterning/genetics , Brain/metabolism , Chick Embryo , Embryo, Nonmammalian/metabolism , Gene Expression Regulation, Developmental , In Situ Hybridization, Fluorescence , Lancelets/metabolism , Male , Mice, Knockout , Models, Biological , Models, Genetic , Neural Tube/metabolism , Vertebrates/metabolism , Zebrafish
19.
Int J Dev Biol ; 61(10-11-12): 655-664, 2017.
Article in English | MEDLINE | ID: mdl-29319114

ABSTRACT

The vertebrate brain is arguably the most complex anatomical and functional structure in nature. During embryonic development, the central nervous system (CNS) undergoes a series of morphogenetic processes that eventually obscure the major axes of the early neural plate to our perception. Notwithstanding this complexity, the "genoarchitecture" of the developing neural tube brings into light homologous regions between brains of different vertebrate species, acting as a molecular barcode of each particular domain. Those homologous regions and their topological inter-relations constitute the ancestral, deeply conserved, bauplan of the vertebrate brain. Remarkably, although simpler, the cephalochordate amphioxus shares multiple features of this bauplan, serving as a privileged reference point to understand the origins of the vertebrate brain. Here, we review the development of the chordate CNS in view of the latest morphological and genoarchitectonic data from amphioxus. This comparison reveals that the amphioxus CNS is far from simple and provides unique insights into the structure of the vertebrate CNS and its evolutionary origins. In particular, we summarize recent research in amphioxus and vertebrates that has challenged views on the major partitions of the vertebrate brain, proposing a novel organization of the chordate CNS bauplan that better reflects developmental and evolutionary data.


Subject(s)
Biological Evolution , Brain/embryology , Central Nervous System/embryology , Lancelets/embryology , Models, Neurological , Animals , Brain/metabolism , Central Nervous System/metabolism , Gene Expression Regulation, Developmental , Lancelets/classification , Lancelets/genetics , Phylogeny , Vertebrates/classification , Vertebrates/embryology , Vertebrates/genetics
20.
Fluids Barriers CNS ; 13: 5, 2016 Mar 15.
Article in English | MEDLINE | ID: mdl-26979569

ABSTRACT

Within the consolidated field of evolutionary development, there is emerging research on evolutionary aspects of central nervous system development and its implications for adult brain structure and function, including behaviour. The central nervous system is one of the most intriguing systems in complex metazoans, as it controls all body and mind functions. Its failure is responsible for a number of severe and largely incurable diseases, including neurological and neurodegenerative ones. Moreover, the evolution of the nervous system is thought to be a critical step in the adaptive radiation of vertebrates. Brain formation is initiated early during development. Most embryological, genetic and evolutionary studies have focused on brain neurogenesis and regionalisation, including the formation and function of organising centres, and the comparison of homolog gene expression and function among model organisms from different taxa. The architecture of the vertebrate brain primordium also reveals the existence of connected internal cavities, the cephalic vesicles, which in fetuses and adults become the ventricular system of the brain. During embryonic and fetal development, brain cavities and ventricles are filled with a complex, protein-rich fluid called cerebrospinal fluid (CSF). However, CSF has not been widely analysed from either an embryological or evolutionary perspective. Recently, it has been demonstrated in higher vertebrates that embryonic cerebrospinal fluid has key functions in delivering diffusible signals and nutrients to the developing brain, thus contributing to the proliferation, differentiation and survival of neural progenitor cells, and to the expansion and patterning of the brain. Moreover, it has been shown that the composition and homeostasis of CSF are tightly controlled in a time-dependent manner from the closure of the anterior neuropore, just before the initiation of primary neurogenesis, up to the formation of functional choroid plexuses. In this review, we draw together existing literature about the formation, function and homeostatic regulation of embryonic cerebrospinal fluid, from the closure of the anterior neuropore to the formation of functional fetal choroid plexuses, from an evolutionary perspective. The relevance of these processes to the normal functions and diseases of adult brain will also be discussed.


Subject(s)
Biological Evolution , Brain/embryology , Brain/growth & development , Cerebrospinal Fluid/physiology , Neurogenesis/physiology , Animals , Cerebrospinal Fluid/chemistry
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