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1.
Nucleic Acids Res ; 46(D1): D1049-D1054, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29186576

RESUMO

AutDB is a deeply annotated resource for exploring the impact of genetic variations associated with autism spectrum disorders (ASD). First released in 2007, AutDB has evolved into a multi-modular resource of diverse types of genetic and functional evidence related to ASD. Current modules include: Human Gene, which annotates all ASD-linked genes and their variants; Animal Model, which catalogs behavioral, anatomical and physiological data from rodent models of ASD; Protein Interaction (PIN), which builds interactomes from direct relationships of protein products of ASD genes; and Copy Number Variant (CNV), which catalogs deletions and duplications of chromosomal loci identified in ASD. A multilevel data-integration strategy is utilized to connect the ASD genes to the components of the other modules. All information in this resource is manually curated by expert scientists from primary scientific publications and is referenced to source articles. AutDB is actively maintained with a rigorous quarterly data release schedule. As of June 2017, AutDB contains detailed annotations for 910 genes, 2197 CNV loci, 1060 rodent models and 38 296 PINs. With its widespread use by the research community, AutDB serves as a reference resource for analysis of large datasets, accelerating ASD research and potentially leading to targeted drug treatments. AutDB is available at http://autism.mindspec.org/autdb/Welcome.do.


Assuntos
Transtorno do Espectro Autista/genética , Bases de Dados Genéticas , Variação Genética , Animais , Transtorno do Espectro Autista/fisiopatologia , Comportamento Animal , Variações do Número de Cópias de DNA , Humanos , Camundongos , Mapeamento de Interação de Proteínas , Ratos
2.
Mol Autism ; 7: 44, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27790361

RESUMO

BACKGROUND: The search for genetic factors underlying autism spectrum disorders (ASD) has led to the identification of hundreds of genes containing thousands of variants that differ in mode of inheritance, effect size, frequency, and function. A major challenge involves assessing the collective evidence in an unbiased, systematic manner for their functional relevance. METHODS: Here, we describe a scoring algorithm for prioritization of candidate genes based on the cumulative strength of evidence for each ASD-associated variant cataloged in AutDB (also known as SFARI Gene). We retrieved data from 889 publications to generate a dataset of 2187 rare and 711 common variants distributed across 461 genes implicated in ASD. Each individual variant was manually annotated with multiple attributes extracted from the original report, followed by score assignment using a set of standardized parameters yielding a single score for each gene. RESULTS: There was a wide variation in scores; SHANK3, CHD8, and ADNP had distinctly higher scores than all other genes in the dataset. Our gene scores were significantly correlated with other recently published rankings of ASD genes (RSpearman = 0.40-0.63; p< 0.0001), providing support for our scoring algorithm. CONCLUSIONS: This new resource, which is freely available, for the first time aggregates on one-platform variants identified from various study types (simplex, multiplex, multigenerational, and consanguineous families), from both common and rare variants, and also incorporates their putative functional consequences to arrive at a genetically and biologically driven ranking scheme. This work represents a major step in moving from simply cataloging autism variants to using data-driven approaches to gain insight into their significance.


Assuntos
Algoritmos , Transtorno do Espectro Autista/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Transtorno do Espectro Autista/fisiopatologia , Bases de Dados Genéticas , Conjuntos de Dados como Assunto , Expressão Gênica , Variação Genética , Humanos , Anotação de Sequência Molecular , Projetos de Pesquisa
3.
J Comp Neurol ; 519(4): 661-89, 2011 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-21246549

RESUMO

Most neurons of the central complex belong to 10 secondary (larvally produced) lineages. In the late larva, undifferentiated axon tracts of these lineages form a primordium in which all of the compartments of the central complex can be recognized as discrete entities. Four posterior lineages (DPMm1, DPMpm1, DPMpm2, and CM4) generate the classes of small-field neurons that interconnect the protocerebral bridge, fan-shaped body, noduli, and ellipsoid body. Three lineages located in the anterior brain, DALv2, BAmv1, and DALcl2, form the large-field neurons of the ellipsoid body and fan-shaped body, respectively. These lineages provide an input channel from the optic tubercle and connect the central complex with adjacent anterior brain compartments. Three lineages in the posterior cortex, CM3, CP2, and DPMpl2, connect the posterior brain neuropil with specific layers of the fan-shaped body. Even though all of the compartments of the central complex are prefigured in the late larval brain by the axon tracts of the above-mentioned lineages, the neuropil differentiates during the first 2 days of the pupal period when terminal branches and synapses of secondary neurons are formed. During this phase the initially straight horizontal layers of the central complex bend in the frontal plane, which produces the characteristic shape of the fan-shaped and ellipsoid body. Our analysis provides a comprehensive picture of the lineages that form the central complex, and will facilitate future studies that address the structure or function of the central complex at the single cell level.


Assuntos
Linhagem da Célula , Drosophila melanogaster/anatomia & histologia , Drosophila melanogaster/crescimento & desenvolvimento , Neurônios/fisiologia , Animais , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento , Proteínas de Drosophila/metabolismo , Metamorfose Biológica , Morfogênese , Neurônios/citologia , Neurônios/metabolismo
4.
J Comp Neurol ; 518(15): 2996-3023, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20533357

RESUMO

The neuropile of the Drosophila brain is subdivided into anatomically discrete compartments. Compartments are rich in terminal neurite branching and synapses; they are the neuropile domains in which signal processing takes place. Compartment boundaries are defined by more or less dense layers of glial cells as well as long neurite fascicles. These fascicles are formed during the larval period, when the approximately 100 neuronal lineages that constitute the Drosophila central brain differentiate. Each lineage forms an axon tract with a characteristic trajectory in the neuropile; groups of spatially related tracts congregate into the brain fascicles that can be followed from the larva throughout metamorphosis into the adult stage. Here we provide a map of the adult brain compartments and the relevant fascicles defining compartmental boundaries. We have identified the neuronal lineages contributing to each fascicle, which allowed us to compare compartments of the larval and adult brain directly. Most adult compartments can be recognized already in the early larval brain, where they form a "protomap" of the later adult compartments. Our analysis highlights the morphogenetic changes shaping the Drosophila brain; the data will be important for studies that link early-acting genetic mechanisms to the adult neuronal structures and circuits controlled by these mechanisms.


Assuntos
Encéfalo/anatomia & histologia , Encéfalo/crescimento & desenvolvimento , Drosophila/anatomia & histologia , Animais , Anticorpos Monoclonais , Axônios/fisiologia , Axônios/ultraestrutura , Mapeamento Encefálico , Caderinas/metabolismo , Quimiocina CX3CL1/metabolismo , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Larva , Vias Neurais/anatomia & histologia , Vias Neurais/crescimento & desenvolvimento , Neuroglia/fisiologia , Neuroglia/ultraestrutura , Sinapses/fisiologia , Sinapses/ultraestrutura
5.
J Neurosci ; 30(22): 7538-53, 2010 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-20519528

RESUMO

The Drosophila brain is formed by an invariant set of lineages, each of which is derived from a unique neural stem cell (neuroblast) and forms a genetic and structural unit of the brain. The task of reconstructing brain circuitry at the level of individual neurons can be made significantly easier by assigning neurons to their respective lineages. In this article we address the automation of neuron and lineage identification. We focused on the Drosophila brain lineages at the larval stage when they form easily recognizable secondary axon tracts (SATs) that were previously partially characterized. We now generated an annotated digital database containing all lineage tracts reconstructed from five registered wild-type brains, at higher resolution and including some that were previously not characterized. We developed a method for SAT structural comparisons based on a dynamic programming approach akin to nucleotide sequence alignment and a machine learning classifier trained on the annotated database of reference SATs. We quantified the stereotypy of SATs by measuring the residual variability of aligned wild-type SATs. Next, we used our method for the identification of SATs within wild-type larval brains, and found it highly accurate (93-99%). The method proved highly robust for the identification of lineages in mutant brains and in brains that differed in developmental time or labeling. We describe for the first time an algorithm that quantifies neuronal projection stereotypy in the Drosophila brain and use the algorithm for automatic neuron and lineage recognition.


Assuntos
Axônios/fisiologia , Linhagem da Célula/fisiologia , Neurônios/classificação , Neurônios/citologia , Algoritmos , Animais , Animais Geneticamente Modificados , Axônios/metabolismo , Encéfalo/citologia , Mapeamento Encefálico , Caspase 3/metabolismo , Linhagem da Célula/genética , Dendritos/metabolismo , Drosophila/anatomia & histologia , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Processamento Eletrônico de Dados/métodos , Embrião não Mamífero , Proteínas de Fluorescência Verde/genética , Processamento de Imagem Assistida por Computador/métodos , Microscopia Confocal/métodos , Modelos Neurológicos , Reprodutibilidade dos Testes , Software
6.
Dev Biol ; 335(2): 289-304, 2009 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19538956

RESUMO

The Drosophila central brain is composed of approximately 100 paired lineages, with most lineages comprising 100-150 neurons. Most lineages have a number of important characteristics in common. Typically, neurons of a lineage stay together as a coherent cluster and project their axons into a coherent bundle visible from late embryo to adult. Neurons born during the embryonic period form the primary axon tracts (PATs) that follow stereotyped pathways in the neuropile. Apoptotic cell death removes an average of 30-40% of primary neurons around the time of hatching. Secondary neurons generated during the larval period form secondary axon tracts (SATs) that typically fasciculate with their corresponding primary axon tract. SATs develop into the long fascicles that interconnect the different compartments of the adult brain. Structurally, we distinguish between three types of lineages: PD lineages, characterized by distinct, spatially separate proximal and distal arborizations; C lineages with arborizations distributed continuously along the entire length of their tract; D lineages that lack proximal arborizations. Arborizations of many lineages, in particular those of the PD type, are restricted to distinct neuropile compartments. We propose that compartments are "scaffolded" by individual lineages, or small groups thereof. Thereby, the relatively small number of primary neurons of each primary lineage set up the compartment map in the late embryo. Compartments grow during the larval period simply by an increase in arbor volume of primary neurons. Arbors of secondary neurons form within or adjacent to the larval compartments, resulting in smaller compartment subdivisions and additional, adult specific compartments.


Assuntos
Axônios , Encéfalo/embriologia , Drosophila/embriologia , Neurônios/citologia , Animais , Apoptose , Encéfalo/citologia , Linhagem da Célula , Imuno-Histoquímica , Modelos Biológicos
7.
Adv Exp Med Biol ; 628: 1-31, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18683635

RESUMO

In this chapter we will start out by describing in more detail the progenitors of the nervous system, the neuroblasts and ganglion mother cells. Subsequently we will survey the generic cell types that make up the developing Drosophila brain, namely neurons, glial cells and tracheal cells. Finally, we will attempt a synopsis of the neuronal connectivity of the larval brain that can be deduced from the analysis of neural lineages and their relationship to neuropile compartments.


Assuntos
Encéfalo/crescimento & desenvolvimento , Drosophila/crescimento & desenvolvimento , Animais , Encéfalo/anatomia & histologia , Encéfalo/citologia , Proliferação de Células , Drosophila/anatomia & histologia , Larva/anatomia & histologia , Larva/citologia , Larva/crescimento & desenvolvimento , Modelos Neurológicos , Morfogênese , Neurônios/citologia , Neurônios/fisiologia , Células-Tronco/citologia , Células-Tronco/fisiologia
8.
Dev Neurobiol ; 67(12): 1669-85, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17577205

RESUMO

Larval behavioral patterns arise in a gradual fashion during late embryogenesis as the innervation of the somatic musculature and connectivity within the central nervous system develops. In this paper, we describe in a quantitative manner the maturation of behavioral patterns. Early movements are locally restricted "twitches" of the body wall, involving single segments or parts of segments. These twitches occur at a low frequency and have low amplitude, reflecting weak muscle contractions. Towards later stages twitches increase in frequency and amplitude and become integrated into coordinated movements of multiple segments. Most noticeable among these is the peristaltic wave of longitudinal segmental contractions by which the larva moves forward or backward. Besides becoming more complex as development proceeds, embryonic movements also acquire a pronounced rhythm. Thus, late embryonic movements occur in bursts, with phases of frequent movement separated by phases of no movement at all; early movements show no such periodicity. These data will serve as a baseline for future studies that address the function of embryonic lethal genes controlling neuronal connectivity and larval behavior. We have analyzed behavioral abnormalities in two embryonic lethal mutations with severe neural defects, tailless (tll), which lacks the protocerebrum, and glial cells missing (gcm), in which glial cells are absent. Our results reveal prominent alterations in embryonic motility for both of these mutations, indicating that the protocerebrum and glial cells play a crucial role in the neural mechanism controlling larval movement in Drosophila.


Assuntos
Encéfalo/embriologia , Drosophila/embriologia , Desenvolvimento Embrionário , Movimento/fisiologia , Músculo Esquelético/embriologia , Animais , Comportamento Animal/fisiologia , Proteínas de Ligação a DNA/genética , Drosophila/genética , Proteínas de Drosophila/genética , Eletrofisiologia , Embrião não Mamífero , Imuno-Histoquímica , Larva/fisiologia , Contração Muscular/fisiologia , Músculo Esquelético/inervação , Músculo Esquelético/fisiologia , Mutação , Neuroglia/metabolismo , Proteínas Repressoras/genética , Fatores de Transcrição/genética
9.
Dev Biol ; 302(1): 169-80, 2007 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-17046740

RESUMO

The Drosophila brain is tracheated by the cerebral trachea, a branch of the first segmental trachea of the embryo. During larval stages the cerebral trachea splits into several main (primary) branches that grow around the neuropile, forming a perineuropilar tracheal plexus (PNP) at the neuropile surface. Five primary tracheal branches whose spatial relationship to brain compartments is relatively invariant can be distinguished, although the exact trajectories and branching pattern of the brain tracheae are surprisingly variable. Immunohistochemical and electron microscopic studies demonstrate that all brain tracheae grow in direct contact with the glial cell processes that surround the neuropile. To investigate the effect of glia on tracheal development, embryos and larvae lacking glial cells as a result of a genetic mutation or a directed ablation were analyzed. In these animals, the tracheal branching pattern was highly abnormal. In particular, the number of secondary branches entering the central neuropile was increased. Wild-type larvae possess only two central tracheae, typically associated with the mushroom body and the antennocerebral tract. In larvae lacking glial cells, six to ten tracheal branches penetrate the neuropile in a variable pattern. This finding indicates that glia-derived signals constrained tracheal growth in the Drosophila brain and restrict the number of branches entering the neuropile.


Assuntos
Drosophila/crescimento & desenvolvimento , Neuroglia/fisiologia , Animais , Encéfalo/irrigação sanguínea , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento , Drosophila/citologia , Imageamento Tridimensional , Larva/citologia , Larva/crescimento & desenvolvimento , Modelos Neurológicos , Neurópilo/citologia
10.
J Neurosci ; 26(20): 5534-53, 2006 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-16707805

RESUMO

The late larval brain consists of embryonically produced primary neurons forming a deep core cortex, surrounded at the surface by approximately 100 secondary lineages. Each secondary lineage forms a tract (secondary lineage tract) with an invariant and characteristic trajectory. Within the neuropile, tracts of neighboring lineages bundle together to form secondary tract systems. In this paper, we visualized secondary lineages by the global marker BP106 (neurotactin), as well as green fluorescent protein-labeled clones and thereby establish a comprehensive digital atlas of secondary lineages. The information contained in this atlas is the location of the lineage within the cortex, the neuropile compartment contacted by the lineage tract, and the projection pattern of the lineage tract within the neuropile. We have digitally mapped the expression pattern of three genes, sine oculis, period, and engrailed into the lineage atlas. The atlas will enable us and others to analyze the phenotype of mutant clones in the larval brain. Mutant clones can only be interpreted if the corresponding wild-type clone is well characterized, and our lineage atlas, which visualizes all wild-type lineages, will provide this information. Secondly, secondary lineage tracts form a scaffold of connections in the neuropile that foreshadows adult nerve connections. Thus, starting from the larval atlas and proceeding forward through pupal development, one will be able to reconstruct adult brain connectivity at a high level of resolution. Third, the atlas can serve as a repository for genes expressed in lineage-specific patterns.


Assuntos
Encéfalo/embriologia , Diferenciação Celular/fisiologia , Linhagem da Célula/fisiologia , Drosophila/embriologia , Neurônios/metabolismo , Células-Tronco/metabolismo , Anatomia Artística/métodos , Animais , Biomarcadores/metabolismo , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento , Mapeamento Encefálico/métodos , Células Clonais/citologia , Células Clonais/metabolismo , Redes de Comunicação de Computadores , Bases de Dados Factuais , Drosophila/citologia , Drosophila/crescimento & desenvolvimento , Proteínas de Drosophila/metabolismo , Proteínas do Olho/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Biblioteca Gênica , Proteínas de Homeodomínio/metabolismo , Processamento de Imagem Assistida por Computador/métodos , Larva/citologia , Larva/crescimento & desenvolvimento , Ilustração Médica , Glicoproteínas de Membrana/metabolismo , Mutação/fisiologia , Neurônios/citologia , Neurópilo/citologia , Neurópilo/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Circadianas Period , Células-Tronco/citologia , Fatores de Transcrição/metabolismo
11.
Dev Biol ; 283(1): 191-203, 2005 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-15907832

RESUMO

Glial cells subserve a number of essential functions during development and function of the Drosophila brain, including the control of neuroblast proliferation, neuronal positioning and axonal pathfinding. Three major classes of glial cells have been identified. Surface glia surround the brain externally. Neuropile glia ensheath the neuropile and form septa within the neuropile that define distinct neuropile compartments. Cortex glia form a scaffold around neuronal cell bodies in the cortex. In this paper we have used global glial markers and GFP-labeled clones to describe the morphology, development and proliferation pattern of the three types of glial cells in the larval brain. We show that both surface glia and cortex glia contribute to the glial layer surrounding the brain. Cortex glia also form a significant part of the glial layer surrounding the neuropile. Glial cell numbers increase slowly during the first half of larval development but show a rapid incline in the third larval instar. This increase results from mitosis of differentiated glia, but, more significantly, from the proliferation of neuroblasts.


Assuntos
Encéfalo/embriologia , Drosophila/embriologia , Morfogênese , Animais , Bromodesoxiuridina , Divisão Celular , Embrião não Mamífero/citologia , Embrião não Mamífero/fisiologia , Larva/fisiologia , Neuroglia/citologia , Neuroglia/fisiologia
12.
Curr Opin Genet Dev ; 14(4): 382-91, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15261654

RESUMO

Digital models of organs, cells and subcellular structures have become important tools in biological and medical research. Reaching far beyond their traditional widespread use as didactic tools, computer-generated models serve as electronic atlases to identify specific elements in complex patterns, and as analytical tools that reveal relationships between such pattern elements that would remain obscure in two-dimensional sections. Digital models also offer the unique opportunity to store and display gene-expression patterns, and pilot studies have been made in several genetic model organisms, including mouse, Drosophila and Caenorhabditis elegans, to construct digital graphic databases intended as repositories for gene-expression data.


Assuntos
Drosophila/embriologia , Desenvolvimento Embrionário/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Modelos Anatômicos , Animais , Sistema Nervoso Central/citologia , Gráficos por Computador , Bases de Dados Factuais , Desenvolvimento Embrionário/genética , Morfogênese
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