RESUMEN
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.
Asunto(s)
Evolución Biológica , Corazón/anatomía & histología , Corazón/crecimiento & desarrollo , Urocordados/anatomía & histología , Urocordados/fisiología , Animales , Linaje de la Célula , Redes Reguladoras de Genes , Locomoción , Miocardio/citología , Miocardio/metabolismo , Urocordados/citología , Urocordados/genéticaRESUMEN
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.
Asunto(s)
Aprendizaje Automático , Edición de ARN , Humanos , Algoritmos , Simulación por Computador , Biología Computacional/métodos , Redes Neurales de la Computación , ARN/genética , ARN/metabolismoRESUMEN
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.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/fisiología , Muerte Celular/genética , Proliferación Celular/genética , Familia de Multigenes/fisiología , Planarias , Animales , Animales Modificados Genéticamente , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Recuento de Células , Mapeo Cromosómico , Regulación del Desarrollo de la Expresión Génica , Homeostasis/genética , Planarias/clasificación , Planarias/citología , Planarias/genética , Planarias/fisiología , Regeneración/genética , Secuencias Repetidas en TándemRESUMEN
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.
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Proteínas 14-3-3 , Encéfalo , Proteínas de Pez Cebra , Pez Cebra , Animales , Humanos , Proteínas 14-3-3/genética , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/fisiopatología , Trastorno Autístico/genética , Trastorno Autístico/fisiopatología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/fisiopatología , Pez Cebra/genética , Proteínas de Pez Cebra/genéticaRESUMEN
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.
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Líquido Cefalorraquídeo/metabolismo , Ojo/metabolismo , Homeostasis , Presión , Presión del Líquido Cefalorraquídeo , HumanosRESUMEN
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.
Asunto(s)
Mitocondrias/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/deficiencia , Retina/metabolismo , Distrofias Retinianas/metabolismo , Células Ganglionares de la Retina/metabolismo , Animales , Autofagia/fisiología , Células Cultivadas , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Mitocondrias/genética , Mitocondrias/ultraestructura , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Retina/ultraestructura , Distrofias Retinianas/genética , Distrofias Retinianas/patología , Células Ganglionares de la Retina/ultraestructura , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/metabolismo , Retinitis Pigmentosa/patologíaRESUMEN
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.
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Canal Anal/embriología , Tracto Gastrointestinal/embriología , Proteínas de Homeodominio/genética , Anfioxos/embriología , Mutación , Cola (estructura animal)/embriología , Factores de Transcripción/genética , Animales , Embrión no Mamífero , Desarrollo Embrionario/genética , Genes Homeobox , Proteínas de Homeodominio/metabolismo , Anfioxos/genética , Factores de Transcripción/metabolismoRESUMEN
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.
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Encéfalo/embriología , Embrión no Mamífero/embriología , Anfioxos/embriología , Tubo Neural/embriología , Vertebrados/embriología , Animales , Evolución Biológica , Tipificación del Cuerpo/genética , Encéfalo/metabolismo , Embrión de Pollo , Embrión no Mamífero/metabolismo , Regulación del Desarrollo de la Expresión Génica , Hibridación Fluorescente in Situ , Anfioxos/metabolismo , Masculino , Ratones Noqueados , Modelos Biológicos , Modelos Genéticos , Tubo Neural/metabolismo , Vertebrados/metabolismo , Pez CebraRESUMEN
The study of the evolutionary origin of vertebrates has been linked to the study of genome duplications since Susumo Ohno suggested that the successful diversification of vertebrate innovations was facilitated by two rounds of whole-genome duplication (2R-WGD) in the stem vertebrate. Since then, studies on the functional evolution of many genes duplicated in the vertebrate lineage have provided the grounds to support experimentally this link. This article reviews cases of gene duplications derived either from the 2R-WGD or from local gene duplication events in vertebrates, analyzing their impact on the evolution of developmental innovations. We analyze how gene regulatory networks can be rewired by the activity of transposable elements after genome duplications, discuss how different mechanisms of duplication might affect the fate of duplicated genes, and how the loss of gene duplicates might influence the fate of surviving paralogs. We also discuss the evolutionary relationships between gene duplication and alternative splicing, in particular in the vertebrate lineage. Finally, we discuss the role that the 2R-WGD might have played in the evolution of vertebrate developmental gene networks, paying special attention to those related to vertebrate key features such as neural crest cells, placodes, and the complex tripartite brain. In this context, we argue that current evidences points that the 2R-WGD may not be linked to the origin of vertebrate innovations, but to their subsequent diversification in a broad variety of complex structures and functions that facilitated the successful transition from peaceful filter-feeding non-vertebrate ancestors to voracious vertebrate predators.
Asunto(s)
Evolución Molecular , Eliminación de Gen , Duplicación de Gen , Vertebrados/genética , Animales , HumanosRESUMEN
Developmental genes are regulated by complex, distantly located cis-regulatory modules (CRMs), often forming genomic regulatory blocks (GRBs) that are conserved among vertebrates and among insects. We have investigated GRBs associated with Iroquois homeobox genes in 39 metazoans. Despite 600 million years of independent evolution, Iroquois genes are linked to ankyrin-repeat-containing Sowah genes in nearly all studied bilaterians. We show that Iroquois-specific CRMs populate the Sowah locus, suggesting that regulatory constraints underlie the maintenance of the Iroquois-Sowah syntenic block. Surprisingly, tetrapod Sowah orthologs are intronless and not associated with Iroquois; however, teleost and elephant shark data demonstrate that this is a derived feature, and that many Iroquois-CRMs were ancestrally located within Sowah introns. Retroposition, gene, and genome duplication have allowed selective elimination of Sowah exons from the Iroquois regulatory landscape while keeping associated CRMs, resulting in large associated gene deserts. These results highlight the importance of CRMs in imposing constraints to genome architecture, even across large phylogenetic distances, and of gene duplication-mediated genetic redundancy to disentangle these constraints, increasing genomic plasticity.
Asunto(s)
Genoma/genética , Proteínas de Homeodominio/genética , Invertebrados/genética , Vertebrados/genética , Secuencia de Aminoácidos , Animales , Evolución Molecular , Duplicación de Gen/genética , Regulación del Desarrollo de la Expresión Génica , Genómica/métodos , Proteínas de Homeodominio/clasificación , Insectos/clasificación , Insectos/embriología , Insectos/genética , Invertebrados/clasificación , Invertebrados/embriología , Datos de Secuencia Molecular , Filogenia , Retroelementos/genética , Homología de Secuencia de Aminoácido , Especificidad de la Especie , Vertebrados/clasificación , Vertebrados/embriologíaRESUMEN
An important question in biology is why some animals are able to regenerate, whereas others are not. The basal chordate amphioxus is uniquely positioned to address the evolution of regeneration. We report here the high regeneration potential of the European amphioxus Branchiostoma lanceolatum. Adults regenerate both anterior and posterior structures, including neural tube, notochord, fin, and muscle. Development of a classifier based on tail regeneration profiles predicts the assignment of young and old adults to their own class with >94% accuracy. The process involves loss of differentiated characteristics, formation of an msx-expressing blastema, and neurogenesis. Moreover, regeneration is linked to the activation of satellite-like Pax3/7 progenitor cells, the extent of which declines with size and age. Our results provide a framework for understanding the evolution and diversity of regeneration mechanisms in vertebrates.
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Cordados no Vertebrados/fisiología , Regeneración/fisiología , Cola (estructura animal)/fisiología , Animales , Cartilla de ADN/genética , Francia , Hibridación in Situ , Larva/fisiología , Factores de Transcripción Paired Box/metabolismo , Células Madre/metabolismo , Factores de TiempoRESUMEN
The vertebrate circulatory system is the most complex vascular system among those of metazoans, with key innovations including a multi-chambered heart and highly specialized blood cells. Invertebrate vessels, on the other hand, consist of hemal spaces between the basal laminae of epithelia. How the evolutionary transition from an invertebrate-type system to the complex vertebrate one occurred is, however, poorly understood. We investigate here the development of the cardiovascular system of the cephalochordate amphioxus Branchiostoma lanceolatum in order to gain insight into the origin of the vertebrate cardiovascular system. The cardiac markers Hand, Csx (Nkx2-5) and Tbx4/5 reveal a broad cardiac-like domain in amphioxus; such a decentralized organization during development parallels that seen in the adult anatomy. Our data therefore support the hypothesis that amphioxus never possessed a proper heart, even transiently during development. We also define a putative hematopoietic domain, supported by the expression of the hematopoietic markers Scl and Pdvegfr. We show that this area is closed to the dorsal aorta anlages, partially linked to excretory tissues, and that its development is regulated by retinoic acid, thus recalling the aorta-gonads-mesonephros (AGM) area of vertebrates. This region probably produces Pdvegfr+ hemal cells, with an important role in amphioxus vessel formation, since treatments with an inhibitor of PDGFR/VEGFR lead to a decrease of Laminin in the basal laminae of developing vessels. Our results point to a chordate origin of hematopoiesis in an AGM-like area from where hemal Pdvegfr+ cells are produced. These Pdvegfr+ cells probably resemble the ancestral chordate blood cells from which the vertebrate endothelium later originated.
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Evolución Biológica , Endotelio/embriología , Hematopoyesis , Vertebrados/embriología , Animales , Biomarcadores/metabolismo , Tipificación del Cuerpo/efectos de los fármacos , Tipificación del Cuerpo/genética , Sistema Cardiovascular/efectos de los fármacos , Sistema Cardiovascular/embriología , Embrión no Mamífero/efectos de los fármacos , Embrión no Mamífero/metabolismo , Endotelio/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Hematopoyesis/efectos de los fármacos , Hematopoyesis/genética , Indoles/farmacología , Larva/efectos de los fármacos , Larva/genética , Modelos Biológicos , Filogenia , Pirroles/farmacología , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Tretinoina/farmacología , Vertebrados/genéticaRESUMEN
Lancelets ('amphioxus') are the modern survivors of an ancient chordate lineage, with a fossil record dating back to the Cambrian period. Here we describe the structure and gene content of the highly polymorphic approximately 520-megabase genome of the Florida lancelet Branchiostoma floridae, and analyse it in the context of chordate evolution. Whole-genome comparisons illuminate the murky relationships among the three chordate groups (tunicates, lancelets and vertebrates), and allow not only reconstruction of the gene complement of the last common chordate ancestor but also partial reconstruction of its genomic organization, as well as a description of two genome-wide duplications and subsequent reorganizations in the vertebrate lineage. These genome-scale events shaped the vertebrate genome and provided additional genetic variation for exploitation during vertebrate evolution.
Asunto(s)
Cordados/genética , Evolución Molecular , Genoma/genética , Animales , Cordados/clasificación , Secuencia Conservada , Elementos Transponibles de ADN/genética , Duplicación de Gen , Genes/genética , Ligamiento Genético , Humanos , Intrones/genética , Cariotipificación , Familia de Multigenes , Filogenia , Polimorfismo Genético/genética , Proteínas/genética , Sintenía , Factores de Tiempo , Vertebrados/clasificación , Vertebrados/genéticaRESUMEN
Specific regulatory states, i.e., sets of expressed transcription factors, define the gene expression capabilities of cells in animal development. Here we explore the functional significance of an unprecedented example of regulatory state conservation from the cnidarian Nematostella to Drosophila, sea urchin, fish, and mammals. Our probe is a deeply conserved cis-regulatory DNA module of the SRY-box B2 (soxB2), recognizable at the sequence level across many phyla. Transphyletic cis-regulatory DNA transfer experiments reveal that the plesiomorphic control function of this module may have been to respond to a regulatory state associated with neuronal differentiation. By introducing expression constructs driven by this module from any phyletic source into the genomes of diverse developing animals, we discover that the regulatory state to which it responds is used at different levels of the neurogenic developmental process, including patterning and development of the vertebrate forebrain and neurogenesis in the Drosophila optic lobe and brain. The regulatory state recognized by the conserved DNA sequence may have been redeployed to different levels of the developmental regulatory program during evolution of complex central nervous systems.
Asunto(s)
Evolución Biológica , Secuencia Conservada/genética , Regulación del Desarrollo de la Expresión Génica , Filogenia , Animales , Animales Modificados Genéticamente , Secuencia de Bases , Encéfalo/embriología , Encéfalo/metabolismo , ADN Intergénico/genética , Drosophila/genética , Elementos de Facilitación Genéticos/genética , Larva/genética , Datos de Secuencia Molecular , Factores de Transcripción SOXB2/genética , Erizos de Mar/genética , Pez Cebra/embriología , Pez Cebra/genéticaRESUMEN
Novel organismal structures in metazoans are often undergirded by complex gene regulatory networks; as such, understanding the emergence of new structures through evolution requires reconstructing the series of evolutionary steps leading to these underlying networks. Here, we reconstruct the step-by-step assembly of the vertebrate splicing network regulated by Nova, a splicing factor that modulates alternative splicing in the vertebrate central nervous system by binding to clusters of YCAY motifs on pre-RNA transcripts. Transfection of human HEK293T cells with Nova orthologs indicated vertebrate-like splicing regulatory activity in bilaterian invertebrates, thus Nova acquired the ability to bind YCAY clusters and perform vertebrate-like splicing modulation at least before the last common ancestor of bilaterians. In situ hybridization studies in several species showed that Nova expression became restricted to CNS later on, during chordate evolution. Finally, comparative genomics studies revealed a diverse history for Nova-regulated exons, with target exons arising through both de novo exon creation and acquisition of YCAY motifs by preexisting exons throughout chordate and vertebrate history. In addition, we find that tissue-specific Nova expression patterns emerged independently in other lineages, suggesting independent assembly of tissue-specific regulatory networks.
Asunto(s)
Empalme Alternativo , Antígenos de Neoplasias/metabolismo , Encéfalo/fisiología , Proteínas del Tejido Nervioso/metabolismo , Proteínas de Unión al ARN/metabolismo , Vertebrados/genética , Animales , Antígenos de Neoplasias/genética , Evolución Molecular , Regulación del Desarrollo de la Expresión Génica , Redes Reguladoras de Genes , Células HEK293 , Humanos , Ratones , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/genética , Antígeno Ventral Neuro-Oncológico , Proteínas de Unión al ARN/genéticaRESUMEN
Cerebrospinal fluid (CSF) has attracted interest as an active signaling milieu that regulates brain development, homeostasis, and course disease. CSF is a nutrient-rich fluid, which also contains growth factors and signaling molecules that regulate multiple cell functions in the central nervous system (CNS). CSF constitution is controlled tightly and constituent concentrations are maintained narrow, depending on developmental stage. From fetal stages to adult life, CSF is produced mainly by the choroid plexus. The development and functional activities of the choroid plexus, and other blood-brain barrier systems in adults, have been extensively analyzed. However, the study of CSF production and homeostasis in embryos from the closure of the anterior neuropore, when the brain cavities become physiologically sealed, to the formation of the functional fetal choroid plexus has been largely neglected. This developmental stage is characterized by tightly controlled morphological and cellular events in the anterior part of the CNS, such as rapid brain anlagen growth and initiation of primary neurogenesis in the neural progenitor cells lining the cavities, events which are driven by specific molecules contained within the embryonic CSF. In this article, we review the existing literature on formation and function of the temporary embryonic blood-CSF barrier, from closure of the anterior neuropore to the formation of functional fetal choroid plexuses, with regard to crucial roles that embryonic CSF plays in neural development.
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Barrera Hematoencefálica/embriología , Barrera Hematoencefálica/fisiología , Líquido Cefalorraquídeo/fisiología , Plexo Coroideo/embriología , Placa Neural/metabolismo , Neurogénesis , Animales , Transporte Biológico , Glucosa/metabolismo , Homeostasis , Humanos , Permeabilidad , Agua/metabolismoRESUMEN
Hox genes, with their similar roles in animals as evolutionarily distant as humans and flies, have fascinated biologists since their discovery nearly 30 years ago. During the last two decades, reports on Hox genes from a still growing number of eumetazoan species have increased our knowledge on the Hox gene contents of a wide range of animal groups. In this review, we summarize the current Hox inventory among deuterostomes, not only in the well-known teleosts and tetrapods, but also in the earlier vertebrate and invertebrate groups. We draw an updated picture of the ancestral repertoires of the different lineages, a sort of "genome Hox bar-code" for most clades. This scenario allows us to infer differential gene or cluster losses and gains that occurred during deuterostome evolution, which might be causally linked to the morphological changes that led to these widely diverse animal taxa. Finally, we focus on the challenging family of posterior Hox genes, which probably originated through independent tandem duplication events at the origin of each of the ambulacrarian, cephalochordate and vertebrate/urochordate lineages.
Asunto(s)
Evolución Molecular , Genes Homeobox , Filogenia , Animales , Cordados/genética , Duplicación de Gen , Especiación Genética , Genoma , Invertebrados/genética , Familia de Multigenes , Vertebrados/genéticaRESUMEN
Tumor-associated fibroblasts (TAF) exert immunosuppressive effects in colorectal carcinoma (CRC), impairing the recognition of tumor cells by effector lymphocytes, including Vδ2 T cells. Herein, we show that CRC-derived TAF can be turned by zoledronic acid (ZA), in soluble form or as antibody-drug conjugate (ADC), into efficient stimulators of Vδ2 T cells. CRC-TAF, obtained from patients, express the epidermal growth factor receptor (EGFR) and the butyrophilin family members BTN3A1/BTN2A1. These butyrophilins mediate the presentation of the phosphoantigens, accumulated in the cells due to ZA effect, to Vδ2 T cells. CRC-TAF exposed to soluble ZA acquired the ability to trigger the proliferation of Vδ2 T cells, in part represented by effector memory cells lacking CD45RA and CD27. In turn, expanded Vδ2 T cells exerted relevant cytotoxic activity towards CRC cells and CRC-TAF when primed with soluble ZA. Of note, also the ADC made of the anti-EGFR cetuximab (Cet) and ZA (Cet-ZA), that we recently described, induced the proliferation of anti-tumor Vδ2 T lymphocytes and their activation against CRC-TAF. These findings indicate that ZA can educate TAF to stimulate effector memory Vδ2 T cells; the Cet-ZA ADC formulation can lead to the precise delivery of ZA to EGFR+ cells, with a double targeting of TAF and tumor cells.
RESUMEN
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.
Asunto(s)
Fosfotransferasas (Aceptor de Grupo Alcohol) , Degeneración Retiniana , Retinitis Pigmentosa , Animales , Humanos , Ratones , Modelos Animales de Enfermedad , Homeostasis , Estrés Oxidativo , Retina , Degeneración Retiniana/genética , Retinitis Pigmentosa/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genéticaRESUMEN
Nitric oxide (NO) is essential to many physiological functions and operates in several signaling pathways. It is not understood how and when the different isoforms of nitric oxide synthase (NOS), the enzyme responsible for NO production, evolved in metazoans. This study investigates the number and structure of metazoan NOS enzymes by genome data mining and direct cloning of Nos genes from the lamprey. In total, 181 NOS proteins are analyzed from 33 invertebrate and 63 vertebrate species. Comparisons among protein and gene structures, combined with phylogenetic and syntenic studies, provide novel insights into how NOS isoforms arose and diverged. Protein domains and gene organization--that is, intron positions and phases--of animal NOS are remarkably conserved across all lineages, even in fast-evolving species. Phylogenetic and syntenic analyses support the view that a proto-NOS isoform was recurrently duplicated in different lineages, acquiring new structural configurations through gains and losses of protein motifs. We propose that in vertebrates a first duplication took place after the agnathan-gnathostome split followed by a paralog loss. A second duplication occurred during early tetrapod evolution, giving rise to the three isoforms--I, II, and III--in current mammals. Overall, NOS family evolution was the result of multiple gene and genome duplication events together with changes in protein architecture.