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1.
Cardiovasc Res ; 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31566660

RESUMO

AIMS: A robust inflammatory response to tissue injury is a necessary part of the repair process but the deposition of scar tissue is a direct downstream consequence of this response in many tissues including the heart. Adult zebrafish not only possess the capacity to regenerate lost cardiomyocytes but also to remodel and resolve an extracellular scar within tissues such as the heart, but this scar resolution process remains poorly understood. This study aims to characterize the scarring and inflammatory responses to cardiac damage in adult zebrafish in full and investigate the role of different inflammatory subsets specifically in scarring and scar removal. METHODS AND RESULTS: Using stable transgenic lines, whole organ imaging and genetic and pharmacological interventions, we demonstrate that multiple inflammatory cell lineages respond to cardiac injury in adult zebrafish. In particular, macrophage subsets (tnfα+ and tnfα-) play prominent roles with manipulation of different phenotypes suggesting that pro-inflammatory (tnfα+) macrophages promote scar deposition following cardiac injury whereas tnfα- macrophages facilitate scar removal during regeneration. Detailed analysis of these specific macrophage subsets reveals crucial roles for Csf1ra in promoting pro-inflammatory macrophage-mediated scar deposition. Additionally, the multifunctional cytokine Osteopontin (Opn) (spp1) is important for initial scar deposition but also for resolution of the inflammatory response and in late-stage ventricular collagen remodelling. CONCLUSIONS: This study demonstrates the importance of a correctly balanced inflammatory response to facilitate scar deposition during repair but also to allow subsequent scar resolution, and full cardiac regeneration, to occur. We have identified Opn as having both pro-fibrotic but also potentially pro-regenerative roles in the adult zebrafish heart, driving Collagen deposition but also controlling inflammatory cell resolution.

2.
Turk J Pediatr ; 61(1): 130-133, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31559735

RESUMO

Albaramki J, Dmour H, Shboul M, Bonnard C, Venkatesh B, Odeh R. Recessive mutation in GALNT3 causes hyperphosphatemic familial tumoral calcinosis associated with chronic recurrent multifocal osteomyelitis. Turk J Pediatr 2019; 61: 130-133. Hyperphosphatemic familial tumoral calcinosis is a rare autosomal recessive disorder that is characterized by persistent hyperphosphatemia and extra-articular calcifications. Three cases were previously reported with hyperphosphatemic familial tumoral calcinosis that were associated with chronic recurrent multifocal osteomyelitis, an autoinflammatory disorder that is characterized by recurrent episodes of bone pain. We describe here an 11-year-old child who was diagnosed with these two conditions and was found to carry a splice site mutation c.1524+1G > A in the GALNT3 gene.

3.
Sci Signal ; 12(584)2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164478

RESUMO

The mineralocorticoid receptor (MR) is a nuclear receptor and part of a large and diverse family of transcription factors that also includes receptors for glucocorticoids, progesterone, androgens, and estrogens. The corticosteroid aldosterone is the physiological activator of the MR in humans and other terrestrial vertebrates; however, its activator is not known in cartilaginous fish, the oldest group of extant jawed vertebrates. Here, we analyzed the ability of corticosteroids and progesterone to activate the full-length MR from the elephant shark (Callorhinchus milii). On the basis of their measured activities, aldosterone, cortisol, 11-deoxycorticosterone, corticosterone, 11-deoxcortisol, progesterone, and 19-norprogesterone are potential physiological mineralocorticoids. However, aldosterone, the physiological mineralocorticoid in humans and other terrestrial vertebrates, is not found in cartilaginous or ray-finned fish. Although progesterone activates MRs in ray-finned fish, progesterone does not activate MRs in humans, amphibians, or alligator, suggesting that during the transition to terrestrial vertebrates, progesterone lost the ability to activate the MR. Both elephant shark MR and human MR are expressed in the brain, heart, ovary, testis, and other nonepithelial tissues, suggesting that MR expression in diverse tissues evolved in the common ancestor of jawed vertebrates. Our data suggest that 19-norprogesterone- and progesterone-activated MR may have unappreciated functions in reproductive physiology.

4.
Int J Mol Sci ; 20(9)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083458

RESUMO

To appraise how evolutionary processes, such as gene duplication and loss, influence an organism's xenobiotic sensitivity is a critical question in toxicology. Of particular importance are gene families involved in the mediation of detoxification responses, such as members of the nuclear receptor subfamily 1 group I (NR1I), the pregnane X receptor (PXR), and the constitutive androstane receptor (CAR). While documented in multiple vertebrate genomes, PXR and CAR display an intriguing gene distribution. PXR is absent in birds and reptiles, while CAR shows a tetrapod-specific occurrence. More elusive is the presence of PXR and CAR gene orthologs in early branching and ecologically-important Chondrichthyes (chimaeras, sharks and rays). Therefore, we investigated various genome projects and use them to provide the first identification and functional characterization of a Chondrichthyan PXR from the chimaera elephant shark (Callorhinchus milii, Holocephali). Additionally, we substantiate the targeted PXR gene loss in Elasmobranchii (sharks and rays). Compared to other vertebrate groups, the chimaera PXR ortholog displays a diverse expression pattern (skin and gills) and a unique activation profile by classical xenobiotic ligands. Our findings provide insights into the molecular landscape of detoxification mechanisms and suggest lineage-specific adaptations in response to xenobiotics in gnathostome evolution.


Assuntos
Elasmobrânquios/classificação , Elasmobrânquios/genética , Evolução Molecular , Redes Reguladoras de Genes , Filogenia , Receptor de Pregnano X/genética , Animais , Células COS , Cercopithecus aethiops , Genes Reporter , Inativação Metabólica/genética , Luciferases/metabolismo , Receptor de Pregnano X/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Sintenia/genética , Ativação Transcricional/genética
6.
BMC Evol Biol ; 18(1): 157, 2018 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-30340454

RESUMO

BACKGROUND: Provision of long-chain polyunsaturated fatty acids (LC-PUFA) in vertebrates occurs through the diet or via endogenous production from C18 precursors through consecutive elongations and desaturations. It has been postulated that the abundance of LC-PUFA in the marine environment has remarkably modulated the gene complement and function of Fads in marine teleosts. In vertebrates two fatty acyl desaturases, namely Fads1 and Fads2, encode ∆5 and ∆6 desaturases, respectively. To fully clarify the evolutionary history of LC-PUFA biosynthesis in vertebrates, we investigated the gene repertoire and function of Fads from species placed at key evolutionary nodes. RESULTS: We demonstrate that functional Fads1Δ5 and Fads2∆6 arose from a tandem gene duplication in the ancestor of vertebrates, since they are present in the Arctic lamprey. Additionally, we show that a similar condition was retained in ray-finned fish such as the Senegal bichir and spotted gar, with the identification of fads1 genes in these lineages. Functional characterisation of the isolated desaturases reveals the first case of a Fads1 enzyme with ∆5 desaturase activity in the Teleostei lineage, the Elopomorpha. In contrast, in Osteoglossomorpha genomes, while no fads1 was identified, two separate fads2 duplicates with ∆6 and ∆5 desaturase activities respectively were uncovered. CONCLUSIONS: We conclude that, while the essential genetic components involved LC-PUFA biosynthesis evolved in the vertebrate ancestor, the full completion of the LC-PUFA biosynthesis pathway arose uniquely in gnathostomes.

7.
Bone ; 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30316000

RESUMO

Analysis of tissue from a 34-years-old male patient from Austrian origin with a history of multiple fractures associated with painful episodes over the carpal, tarsal and at the end of the long bones respectively is presented. Radiographic images and axial 3DCT scans showed widespread defects in trabecular bone architecture and ill-defined cortices over these skeletal sites in the form of discrete cystic-like lesions. Family history indicated two sisters (one half and one full biological sisters) also with a history of fractures. Whole exome sequencing revealed two heterozygous missense mutations in TYROBP (MIM 604142; NM_003332.3) gene encoding for a cell-surface adaptor protein, which is part of a signaling complex triggering activation of immune responses. It is expressed in cells of the ectoderm cell linage such as NK and dendritic cells, macrophages, monocytes, myeloid cells, microglia cells and osteoclasts. The phenotype and genotype of the patient were consistent with the diagnosis of Nasu-Hakola disease (NHD) (OMIM 221770). Investigations at the bone material level of a transiliac bone biopsy sample from the patient using polarized light microscopy and backscatter electron imaging revealed disordered lamellar collagen fibril arrangement and extensively increased matrix mineralization. These findings are the first bone material data in a patient with NHD and point toward an osteoclast defect involvement in this genetic condition.

8.
Front Neurosci ; 12: 607, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30237760

RESUMO

The neuropeptide gonadotropin-releasing hormone (GnRH) plays an important role in the control of reproductive functions. Vertebrates possess multiple GnRH forms that are classified into three main groups, namely GnRH1, GnRH2, and GnRH3. In order to gain more insights into the GnRH gene family in vertebrates, we sought to identify which paralogs of this family are present in cartilaginous fish. For this purpose, we searched the genomes and/or transcriptomes of three representative species of this group, the small-spotted catshark, Scyliorhinus canicula, the whale shark, Rhincodon typus and the elephant shark Callorhinchus milii. In each species, we report the identification of three GnRH genes. In catshark and whale shark, phylogenetic and synteny analysis showed that these three genes correspond to GnRH1, GnRH2, and GnRH3. In both species, GnRH1 was found to encode a novel form of GnRH whose primary structure was determined as follows: QHWSFDLRPG. In elephant shark, the three genes correspond to GnRH1a and GnRH1b, two copies of the GnRH1 gene, plus GnRH2. 3D structure prediction of the chondrichthyan GnRH-associated peptides (GAPs) revealed that catshark GAP1, GAP2, and elephant shark GAP2 peptides exhibit a helix-loop-helix (HLH) structure. This structure observed for many osteichthyan GAP1 and GAP2, may convey GAP biological activity. This HLH structure could not be observed for elephant shark GAP1a and GAP1b. As for all other GAP3 described so far, no typical 3D HLH structure was observed for catshark nor whale shark GAP3. RT-PCR analysis revealed that GnRH1, GnRH2, and GnRH3 genes are differentially expressed in the catshark brain. GnRH1 mRNA appeared predominant in the diencephalon while GnRH2 and GnRH3 mRNAs seemed to be most abundant in the mesencephalon and telencephalon, respectively. Taken together, our results show that the GnRH gene repertoire of the vertebrate ancestor was entirely conserved in the chondrichthyan lineage but that the GnRH3 gene was probably lost in holocephali. They also suggest that the three GnRH neuronal systems previously described in the brain of bony vertebrates are also present in cartilaginous fish.

9.
BMC Med Genet ; 19(1): 125, 2018 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-30041615

RESUMO

BACKGROUND: Cenani-Lenz Syndactyly (CLS) syndrome is a rare autosomal recessive disorder characterized by syndactyly and oligodactyly of fingers and toes, disorganization and fusion of metacarpals, metatarsals and phalanges, radioulnar synostosis and mesomelic shortness of the limbs, with lower limbs usually being much less affected than upper limbs. CASE PRESENTATION: we report here two patients, born to consanguineous Sri Lankan parents, present with bilateral postaxial oligodactyly limited to upper limbs. While the proband has no noticeable facial dysmorphism, renal impairments or cognitive impairments, his affected sister displays a few mild facial dysmorphic features. Whole exome sequencing of the proband showed a novel deleterious homozygous mutation (c.1348A > G) in the LRP4 gene, resulting in an Ile450-to-Val (I450V) substitution. CONCLUSION: This recessive mutation in LRP4 confirmed the diagnosis of CLS syndrome in two patients present with isolated hand syndactyly. This is the first reported case of CLS syndrome in a family of Sri Lankan origin.

10.
Proc Natl Acad Sci U S A ; 115(24): 6249-6254, 2018 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-29760103

RESUMO

Our understanding of phylogenetic relationships among bony fishes has been transformed by analysis of a small number of genes, but uncertainty remains around critical nodes. Genome-scale inferences so far have sampled a limited number of taxa and genes. Here we leveraged 144 genomes and 159 transcriptomes to investigate fish evolution with an unparalleled scale of data: >0.5 Mb from 1,105 orthologous exon sequences from 303 species, representing 66 out of 72 ray-finned fish orders. We apply phylogenetic tests designed to trace the effect of whole-genome duplication events on gene trees and find paralogy-free loci using a bioinformatics approach. Genome-wide data support the structure of the fish phylogeny, and hypothesis-testing procedures appropriate for phylogenomic datasets using explicit gene genealogy interrogation settle some long-standing uncertainties, such as the branching order at the base of the teleosts and among early euteleosts, and the sister lineage to the acanthomorph and percomorph radiations. Comprehensive fossil calibrations date the origin of all major fish lineages before the end of the Cretaceous.


Assuntos
Peixes/genética , Genoma/genética , Transcriptoma/genética , Animais , Evolução Molecular , Éxons/genética , Fósseis , Duplicação Gênica/genética , Genômica/métodos , Modelos Genéticos , Filogenia
11.
Eur J Med Genet ; 61(10): 585-595, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29605658

RESUMO

Mutations in CPLANE1 (previously known as C5orf42) cause Oral-Facial-Digital Syndrome type VI (OFD6) as well as milder Joubert syndrome (JS) phenotypes. Seven new cases from five unrelated families diagnosed with pure OFD6 were systematically examined. Based on the clinical manifestations of these patients and those described in the literature, we revised the diagnostic features of OFD6 and include the seven most common characteristics: 1) molar tooth sign, 2) tongue hamartoma and/or lobulated tongue, 3) additional frenula, 4) mesoaxial polydactyly of hands, 5) preaxial polydactyly of feet, 6) syndactyly and/or bifid toe, and 7) hypothalamic hamartoma. By whole or targeted exome sequencing, we identified seven novel germline recessive mutations in CPLANE1, including missense, nonsense, frameshift and canonical splice site variants, all causing OFD6 in these patients. Since CPLANE1 is also mutated in JS patients, we examined whether a genotype-phenotype correlation could be established. We gathered and compared 46 biallelic CPLANE1 mutations reported in 32 JS and 26 OFD6 patients. Since no clear correlation between paired genotypes and clinical outcomes could be determined, we concluded that patient's genetic background and gene modifiers may modify the penetrance and expressivity of CPLANE1 causal alleles. To conclude, our study provides a comprehensive view of the phenotypic range, the genetic basis and genotype-phenotype association in OFD6 and JS. The updated phenotype scoring system together with the identification of new CPLANE1 mutations will help clinicians and geneticists reach a more accurate diagnosis for JS-related disorders.

12.
Proc Natl Acad Sci U S A ; 115(14): E3211-E3220, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29555777

RESUMO

Cytidine deaminases of the AID/APOBEC family catalyze C-to-U nucleotide transitions in mRNA or DNA. Members of the APOBEC3 branch are involved in antiviral defense, whereas AID contributes to diversification of antibody repertoires in jawed vertebrates via somatic hypermutation, gene conversion, and class switch recombination. In the extant jawless vertebrate, the lamprey, two members of the AID/APOBEC family are implicated in the generation of somatic diversity of the variable lymphocyte receptors (VLRs). Expression studies linked CDA1 and CDA2 genes to the assembly of VLRA/C genes in T-like cells and the VLRB genes in B-like cells, respectively. Here, we identify and characterize several CDA1-like genes in the larvae of different lamprey species and demonstrate that these encode active cytidine deaminases. Structural comparisons of the CDA1 variants highlighted substantial differences in surface charge; this observation is supported by our finding that the enzymes require different conditions and substrates for optimal activity in vitro. Strikingly, we also found that the number of CDA-like genes present in individuals of the same species is variable. Nevertheless, irrespective of the number of different CDA1-like genes present, all lamprey larvae have at least one functional CDA1-related gene encoding an enzyme with predicted structural and chemical features generally comparable to jawed vertebrate AID. Our findings suggest that, similar to APOBEC3 branch expansion in jawed vertebrates, the AID/APOBEC family has undergone substantial diversification in lamprey, possibly indicative of multiple distinct biological roles.


Assuntos
Desaminase APOBEC-1/genética , Citidina Desaminase/classificação , Citidina Desaminase/genética , Variações do Número de Cópias de DNA , Lampreias/genética , Linfócitos/imunologia , Receptores de Antígenos/genética , Desaminase APOBEC-1/química , Desaminase APOBEC-1/imunologia , Sequência de Aminoácidos , Animais , Citidina Desaminase/química , Citidina Desaminase/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Conformação Proteica , Receptores de Antígenos/classificação , Homologia de Sequência , Sequenciamento Completo do Genoma
13.
Annu Rev Anim Biosci ; 6: 47-68, 2018 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-29447475

RESUMO

Boasting nearly 30,000 species, teleosts account for half of all extant vertebrates and approximately 98% of all ray-finned fish species (Actinopterygii). Teleosts are also the largest and most diverse group of vertebrates, exhibiting an astonishing level of morphological, physiological, and behavioral diversity. Previous studies had indicated that the teleost lineage has experienced an additional whole-genome duplication event. Recent comparative genomic analyses of teleosts and other bony vertebrates using spotted gar (a nonteleost ray-finned fish) and elephant shark (a cartilaginous fish) as outgroups have revealed several divergent features of teleost genomes. These include an accelerated evolutionary rate of protein-coding and nucleotide sequences, a higher rate of intron turnover, loss of many potential cis-regulatory elements and shorter conserved syntenic blocks. A combination of these divergent genomic features might have contributed to the evolution of the amazing phenotypic diversity and morphological innovations of teleosts.

14.
Cell ; 172(4): 667-682.e15, 2018 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-29425489

RESUMO

Walking is the predominant locomotor behavior expressed by land-dwelling vertebrates, but it is unknown when the neural circuits that are essential for limb control first appeared. Certain fish species display walking-like behaviors, raising the possibility that the underlying circuitry originated in primitive marine vertebrates. We show that the neural substrates of bipedalism are present in the little skate Leucoraja erinacea, whose common ancestor with tetrapods existed ∼420 million years ago. Leucoraja exhibits core features of tetrapod locomotor gaits, including left-right alternation and reciprocal extension-flexion of the pelvic fins. Leucoraja also deploys a remarkably conserved Hox transcription factor-dependent program that is essential for selective innervation of fin/limb muscle. This network encodes peripheral connectivity modules that are distinct from those used in axial muscle-based swimming and has apparently been diminished in most modern fish. These findings indicate that the circuits that are essential for walking evolved through adaptation of a genetic regulatory network shared by all vertebrates with paired appendages. VIDEO ABSTRACT.

15.
Proc Biol Sci ; 284(1863)2017 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-28931746

RESUMO

Studies of the voltage-gated sodium (Nav) channels of extant gnathostomes have made it possible to deduce that ancestral gnathostomes possessed four voltage-gated sodium channel genes derived from a single ancestral chordate gene following two rounds of genome duplication early in vertebrates. We investigated the Nav gene family in two species of lampreys (the Japanese lamprey Lethenteron japonicum and sea lamprey Petromyzon marinus) (jawless vertebrates-agnatha) and compared them with those of basal vertebrates to better understand the origin of Nav genes in vertebrates. We noted six Nav genes in both lamprey species, but orthology with gnathostome (jawed vertebrate) channels was inconclusive. Surprisingly, the Nav2 gene, ubiquitously found in invertebrates and believed to have been lost in vertebrates, is present in lampreys, elephant shark (Callorhinchus milii) and coelacanth (Latimeria chalumnae). Despite repeated duplication of the Nav1 family in vertebrates, Nav2 is only in single copy in those vertebrates in which it is retained, and was independently lost in ray-finned fishes and tetrapods. Of the other five Nav channel genes, most were expressed in brain, one in brain and heart, and one exclusively in skeletal muscle. Invertebrates do not express Nav channel genes in muscle. Thus, early in the vertebrate lineage Nav channels began to diversify and different genes began to express in heart and muscle.


Assuntos
Evolução Molecular , Proteínas de Peixes/genética , Duplicação Gênica , Lampreias/genética , Canais de Sódio Disparados por Voltagem/genética , Animais , Filogenia
16.
Am J Hum Genet ; 101(3): 391-403, 2017 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-28886341

RESUMO

In five separate families, we identified nine individuals affected by a previously unidentified syndrome characterized by growth retardation, spine malformation, facial dysmorphisms, and developmental delays. Using homozygosity mapping, array CGH, and exome sequencing, we uncovered bi-allelic loss-of-function CDK10 mutations segregating with this disease. CDK10 is a protein kinase that partners with cyclin M to phosphorylate substrates such as ETS2 and PKN2 in order to modulate cellular growth. To validate and model the pathogenicity of these CDK10 germline mutations, we generated conditional-knockout mice. Homozygous Cdk10-knockout mice died postnatally with severe growth retardation, skeletal defects, and kidney and lung abnormalities, symptoms that partly resemble the disease's effect in humans. Fibroblasts derived from affected individuals and Cdk10-knockout mouse embryonic fibroblasts (MEFs) proliferated normally; however, Cdk10-knockout MEFs developed longer cilia. Comparative transcriptomic analysis of mutant and wild-type mouse organs revealed lipid metabolic changes consistent with growth impairment and altered ciliogenesis in the absence of CDK10. Our results document the CDK10 loss-of-function phenotype and point to a function for CDK10 in transducing signals received at the primary cilia to sustain embryonic and postnatal development.


Assuntos
Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/fisiologia , Deficiências do Desenvolvimento/genética , Transtornos do Crescimento/genética , Mutação , Coluna Vertebral/anormalidades , Coluna Vertebral/patologia , Animais , Ciclo Celular , Proliferação de Células , Células Cultivadas , Criança , Pré-Escolar , Cílios/metabolismo , Cílios/patologia , Deficiências do Desenvolvimento/patologia , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Transtornos do Crescimento/patologia , Humanos , Lactente , Masculino , Camundongos , Camundongos Knockout , Linhagem , Fosforilação , Transdução de Sinais , Coluna Vertebral/metabolismo
17.
Nat Commun ; 8(1): 702, 2017 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-28951542

RESUMO

T-lineage committed precursor thymocytes are screened by a fate-determination process mediated via T cell receptor (TCR) signals for differentiation into distinct lineages. However, it remains unclear whether any antecedent event is required to couple TCR signals with the transcriptional program governing lineage decisions. Here we show that Bcl11b, known as a T-lineage commitment factor, is essential for proper expression of ThPOK and Runx3, central regulators for the CD4-helper/CD8-cytotoxic lineage choice. Loss of Bcl11b results in random expression of these factors and, thereby, lineage scrambling that is disconnected from TCR restriction by MHC. Initial Thpok repression by Bcl11b prior to the pre-selection stage is independent of a known silencer for Thpok, and requires the last zinc-finger motif in Bcl11b protein, which by contrast is dispensable for T-lineage commitment. Collectively, our findings shed new light on the function of Bcl11b in priming lineage-specifying genes to integrate TCR signals into subsequent transcriptional regulatory mechanisms.CD4 and CD8 T cells develop in the thymus with their transcription programs controlled by ThPOK and Runx3, respectively. Here the authors show that a pre-commitment event modulated by the transcription factor, Bcl11b, is required for the proper expression of ThPOK and Runx3 and correct CD4/CD8 lineage commitment.


Assuntos
Diferenciação Celular/genética , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Proteínas Repressoras/genética , Linfócitos T Citotóxicos/citologia , Linfócitos T Auxiliares-Indutores/citologia , Timócitos/citologia , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Animais , Linhagem da Célula , Regulação da Expressão Gênica , Camundongos , Receptores de Antígenos de Linfócitos T/genética
18.
Proc Natl Acad Sci U S A ; 114(34): 9146-9151, 2017 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-28784804

RESUMO

ParaHox genes (Gsx, Pdx, and Cdx) are an ancient family of developmental genes closely related to the Hox genes. They play critical roles in the patterning of brain and gut. The basal chordate, amphioxus, contains a single ParaHox cluster comprising one member of each family, whereas nonteleost jawed vertebrates contain four ParaHox genomic loci with six or seven ParaHox genes. Teleosts, which have experienced an additional whole-genome duplication, contain six ParaHox genomic loci with six ParaHox genes. Jawless vertebrates, represented by lampreys and hagfish, are the most ancient group of vertebrates and are crucial for understanding the origin and evolution of vertebrate gene families. We have previously shown that lampreys contain six Hox gene loci. Here we report that lampreys contain only two ParaHox gene clusters (designated as α- and ß-clusters) bearing five ParaHox genes (Gsxα, Pdxα, Cdxα, Gsxß, and Cdxß). The order and orientation of the three genes in the α-cluster are identical to that of the single cluster in amphioxus. However, the orientation of Gsxß in the ß-cluster is inverted. Interestingly, Gsxß is expressed in the eye, unlike its homologs in jawed vertebrates, which are expressed mainly in the brain. The lamprey Pdxα is expressed in the pancreas similar to jawed vertebrate Pdx genes, indicating that the pancreatic expression of Pdx was acquired before the divergence of jawless and jawed vertebrate lineages. It is likely that the lamprey Pdxα plays a crucial role in pancreas specification and insulin production similar to the Pdx of jawed vertebrates.


Assuntos
Genes Homeobox/genética , Lampreias/genética , Família Multigênica , Vertebrados/genética , Sequência de Aminoácidos , Animais , Evolução Molecular , Proteínas de Peixes/genética , Perfilação da Expressão Gênica/métodos , Proteínas de Homeodomínio/classificação , Proteínas de Homeodomínio/genética , Filogenia , Homologia de Sequência de Aminoácidos , Vertebrados/classificação
19.
Gigascience ; 6(6): 1-6, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28444302

RESUMO

Background: The lined seahorse, Hippocampus erectus , is an Atlantic species and mainly inhabits shallow sea beds or coral reefs. It has become very popular in China for its wide use in traditional Chinese medicine. In order to improve the aquaculture yield of this valuable fish species, we are trying to develop genomic resources for assistant selection in genetic breeding. Here, we provide whole genome sequencing, assembly, and gene annotation of the lined seahorse, which can enrich genome resource and further application for its molecular breeding. A total of 174.6 Gb (Gigabase) raw DNA sequences were generated by the Illumina Hiseq2500 platform. The final assembly of the lined seahorse genome is around 458 Mb, representing 94% of the estimated genome size (489 Mb by k-mer analysis). The contig N50 and scaffold N50 reached 14.57 kb and 1.97 Mb, respectively. Quality of the assembled genome was assessed by BUSCO with prediction of 85% of the known vertebrate genes and evaluated using the de novo assembled RNA-seq transcripts to prove a high mapping ratio (more than 99% transcripts could be mapped to the assembly). Using homology-based, de novo and transcriptome-based prediction methods, we predicted 20 788 protein-coding genes in the generated assembly, which is less than our previously reported gene number (23 458) of the tiger tail seahorse ( H. comes ). We report a draft genome of the lined seahorse. These generated genomic data are going to enrich genome resource of this economically important fish, and also provide insights into the genetic mechanisms of its iconic morphology and male pregnancy behavior.


Assuntos
Mapeamento de Sequências Contíguas/métodos , Genoma , Análise de Sequência de DNA/métodos , Smegmamorpha/genética , Animais , Aquicultura , China , Tamanho do Genoma , Anotação de Sequência Molecular , Filogenia , Seleção Artificial
20.
Am J Hum Genet ; 100(4): 659-665, 2017 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-28318499

RESUMO

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4-deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC.


Assuntos
Artrogripose/genética , Proteínas da Matriz Extracelular/genética , Mutação , Células de Schwann/metabolismo , Artrogripose/diagnóstico , Artrogripose/patologia , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Bainha de Mielina/metabolismo , Linhagem
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