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1.
BMC Genomics ; 24(1): 725, 2023 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-38036964

RESUMEN

In recent single-cell -omics studies, both the differential activity of transcription factors regulating cell fate determination and differential genome activation have been tested for utility as descriptors of cell types. Naturally, genome accessibility and gene expression are interlinked. To understand the variability in genomic feature activation in the GABAergic neurons of different spatial origins, we have mapped accessible chromatin regions and mRNA expression in single cells derived from the developing mouse central nervous system (CNS). We first defined a reference set of open chromatin regions for scATAC-seq read quantitation across samples, allowing comparison of chromatin accessibility between brain regions and cell types directly. Second, we integrated the scATAC-seq and scRNA-seq data to form a unified resource of transcriptome and chromatin accessibility landscape for the cell types in di- and telencephalon, midbrain and anterior hindbrain of E14.5 mouse embryo. Importantly, we implemented resolution optimization at the clustering, and automatized the cell typing step. We show high level of concordance between the cell clustering based on the chromatin accessibility and the transcriptome in analyzed neuronal lineages, indicating that both genome and transcriptome features can be used for cell type definition. Hierarchical clustering by the similarity in accessible chromatin reveals that the genomic feature activation correlates with neurotransmitter phenotype, selector gene expression, cell differentiation stage and neuromere origins.


Asunto(s)
Cromatina , Factores de Transcripción , Animales , Ratones , Cromatina/genética , Diferenciación Celular/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Genoma , Encéfalo/metabolismo , Análisis de la Célula Individual
2.
Front Neurosci ; 16: 976209, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36148148

RESUMEN

The Substantia Nigra pars reticulata (SNpr) is the major information output site of the basal ganglia network and instrumental for the activation and adjustment of movement, regulation of the behavioral state and response to reward. Due to both overlapping and unique input and output connections, the SNpr might also have signal integration capacity and contribute to action selection. How the SNpr regulates these multiple functions remains incompletely understood. The SNpr is located in the ventral midbrain and is composed primarily of inhibitory GABAergic projection neurons that are heterogeneous in their properties. In addition, the SNpr contains smaller populations of other neurons, including glutamatergic neurons. Here, we discuss regionalization of the SNpr, in particular the division of the SNpr neurons to anterior (aSNpr) and posterior (pSNpr) subtypes, which display differences in many of their features. We hypothesize that unique developmental and molecular characteristics of the SNpr neuron subtypes correlate with both region-specific connections and notable functional specializations of the SNpr. Variation in both the genetic control of the SNpr neuron development as well as signals regulating cell migration and axon guidance may contribute to the functional diversity of the SNpr neurons. Therefore, insights into the various aspects of differentiation of the SNpr neurons can increase our understanding of fundamental brain functions and their defects in neurological and psychiatric disorders, including movement and mood disorders, as well as epilepsy.

3.
Development ; 149(14)2022 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-35815619

RESUMEN

The midbrain reticular formation (MRF) is a mosaic of diverse GABAergic and glutamatergic neurons that have been associated with a variety of functions, including sleep regulation. However, the molecular characteristics and development of MRF neurons are poorly understood. As the transcription factor, Gata2 is required for the development of all GABAergic neurons derived from the embryonic mouse midbrain, we hypothesized that the genes expressed downstream of Gata2 could contribute to the diversification of GABAergic neuron subtypes in this brain region. Here, we show that Gata2 is required for the expression of several GABAergic lineage-specific transcription factors, including Nkx2-2 and Skor2, which are co-expressed in a restricted group of post-mitotic GABAergic precursors in the MRF. Both Gata2 and Nkx2-2 function is required for Skor2 expression in GABAergic precursors. In the adult mouse and rat midbrain, Nkx2-2-and Skor2-expressing GABAergic neurons locate at the boundary of the ventrolateral periaqueductal gray and the MRF, an area containing REM-off neurons regulating REM sleep. In addition to the characteristic localization, Skor2+ cells increase their activity upon REM-sleep inhibition, send projections to the dorsolateral pons, a region associated with sleep control, and are responsive to orexins, consistent with the known properties of midbrain REM-off neurons.


Asunto(s)
Neuronas GABAérgicas , Sueño REM , Animales , Neuronas GABAérgicas/metabolismo , Factor de Transcripción GATA2/genética , Factor de Transcripción GATA2/metabolismo , Proteína Homeobox Nkx-2.2/metabolismo , Mesencéfalo , Ratones , Proteínas del Tejido Nervioso/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Ratas , Sueño/fisiología , Sueño REM/fisiología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
4.
Science ; 374(6568): 717-723, 2021 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-34735222

RESUMEN

The evolutionary origin of metazoan cell types such as neurons and muscles is not known. Using whole-body single-cell RNA sequencing in a sponge, an animal without nervous system and musculature, we identified 18 distinct cell types. These include nitric oxide­sensitive contractile pinacocytes, amoeboid phagocytes, and secretory neuroid cells that reside in close contact with digestive choanocytes that express scaffolding and receptor proteins. Visualizing neuroid cells by correlative x-ray and electron microscopy revealed secretory vesicles and cellular projections enwrapping choanocyte microvilli and cilia. Our data show a communication system that is organized around sponge digestive chambers, using conserved modules that became incorporated into the pre- and postsynapse in the nervous systems of other animals.


Asunto(s)
Evolución Biológica , Poríferos/citología , Animales , Comunicación Celular , Extensiones de la Superficie Celular/ultraestructura , Cilios/fisiología , Cilios/ultraestructura , Sistema Digestivo/citología , Mesodermo/citología , Sistema Nervioso/citología , Fenómenos Fisiológicos del Sistema Nervioso , Óxido Nítrico/metabolismo , Poríferos/genética , Poríferos/metabolismo , RNA-Seq , Vesículas Secretoras/ultraestructura , Transducción de Señal , Análisis de la Célula Individual , Transcriptoma
5.
Cell Rep ; 33(2): 108268, 2020 10 13.
Artículo en Inglés | MEDLINE | ID: mdl-33053343

RESUMEN

Tegmental nuclei in the ventral midbrain and anterior hindbrain control motivated behavior, mood, memory, and movement. These nuclei contain inhibitory GABAergic and excitatory glutamatergic neurons, whose molecular diversity and development remain largely unraveled. Many tegmental neurons originate in the embryonic ventral rhombomere 1 (r1), where GABAergic fate is regulated by the transcription factor (TF) Tal1. We used single-cell mRNA sequencing of the mouse ventral r1 to characterize the Tal1-dependent and independent neuronal precursors. We describe gene expression dynamics during bifurcation of the GABAergic and glutamatergic lineages and show how active Notch signaling promotes GABAergic fate selection in post-mitotic precursors. We identify GABAergic precursor subtypes that give rise to distinct tegmental nuclei and demonstrate that Sox14 and Zfpm2, two TFs downstream of Tal1, are necessary for the differentiation of specific tegmental GABAergic neurons. Our results provide a framework for understanding the development of cellular diversity in the tegmental nuclei.


Asunto(s)
Neuronas GABAérgicas/metabolismo , Ácido Glutámico/metabolismo , Rombencéfalo/metabolismo , Tegmento Mesencefálico/metabolismo , Animales , Diferenciación Celular , Linaje de la Célula , Proteínas de Unión al ADN/metabolismo , Núcleo Dorsal del Rafe/metabolismo , Embrión de Mamíferos/citología , Femenino , Proteína Forkhead Box O1/metabolismo , Proteínas de Homeodominio/metabolismo , Masculino , Ratones Endogámicos C57BL , Células-Madre Neurales/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Notch/metabolismo , Factores de Transcripción SOXB2/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína 1 de la Leucemia Linfocítica T Aguda/metabolismo , Factores de Transcripción/metabolismo
6.
BMC Biol ; 17(1): 81, 2019 10 22.
Artículo en Inglés | MEDLINE | ID: mdl-31640768

RESUMEN

BACKGROUND: During early development, patterns of cell division-embryonic cleavage-accompany the gradual restriction of blastomeres to specific cell fates. In Spiralia, which include annelids, mollusks, and flatworms, "spiral cleavage" produces a highly stereotypic, spiral-like arrangement of blastomeres and swimming trochophore-type larvae with rotational (spiral) symmetry. However, starting at larval stages, spiralian larvae acquire elements of bilateral symmetry, before they metamorphose into fully bilateral juveniles. How this spiral-to-bilateral transition occurs is not known and is especially puzzling for the early differentiating brain and head sensory organs, which emerge directly from the spiral cleavage pattern. Here we present the developmental cell lineage of the Platynereis larval episphere. RESULTS: Live-imaging recordings from the zygote to the mid-trochophore stage (~ 30 hpf) of the larval episphere of the marine annelid Platynereis dumerilii reveal highly stereotypical development and an invariant cell lineage of early differentiating cell types. The larval brain and head sensory organs develop from 11 pairs of bilateral founders, each giving rise to identical clones on the right and left body sides. Relating the origin of each bilateral founder pair back to the spiral cleavage pattern, we uncover highly divergent origins: while some founder pairs originate from corresponding cells in the spiralian lineage on each body side, others originate from non-corresponding cells, and yet others derive from a single cell within one quadrant. Integrating lineage and gene expression data for several embryonic and larval stages, we find that the conserved head patterning genes otx and six3 are expressed in bilateral founders representing divergent lineage histories and giving rise to early differentiating cholinergic neurons and head sensory organs, respectively. CONCLUSIONS: We present the complete developmental cell lineage of the Platynereis larval episphere, and thus the first comprehensive account of the spiral-to-bilateral transition in a developing spiralian. The bilateral symmetry of the head emerges from pairs of bilateral founders, similar to the trunk; however, the head founders are more numerous and show striking left-right asymmetries in lineage behavior that we relate to differential gene expression.


Asunto(s)
Tipificación del Cuerpo , Encéfalo/embriología , Linaje de la Célula , Desarrollo Embrionario , Poliquetos/embriología , Animales , Encéfalo/crecimiento & desarrollo , Diferenciación Celular/fisiología , Embrión no Mamífero/embriología , Larva/crecimiento & desarrollo , Poliquetos/crecimiento & desarrollo
7.
Curr Opin Neurobiol ; 56: 144-152, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30826503

RESUMEN

Major questions in the evolution of neurons and nervous systems remain unsolved, such as the origin of the first neuron, the possible convergent evolution of neuronal phenotypes, and the transition from a relatively simple decentralized nerve net to the complex, centralized nervous systems found in modern bilaterian animals. In recent years, comparative single-cell transcriptomics has opened up new research avenues addressing these issues. Here, we review recent conceptual progress toward an evolutionary definition of cell types, and how it facilitates the identification and large-scale comparison of neuronal types and neuron type families from single-cell data - with the family of GABAergic neurons in distinct parts of the vertebrate forebrain as prime example. We also highlight strategies to infer cell type-specific innovation, so-called apomeres, from single-cell data.


Asunto(s)
Evolución Biológica , Sistema Nervioso , Animales , Neuronas GABAérgicas , Red Nerviosa
8.
Mol Biol Evol ; 35(5): 1047-1062, 2018 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-29373712

RESUMEN

Animal bodies comprise diverse arrays of cells. To characterize cellular identities across an entire body, we have compared the transcriptomes of single cells randomly picked from dissociated whole larvae of the marine annelid Platynereis dumerilii. We identify five transcriptionally distinct groups of differentiated cells, each expressing a unique set of transcription factors and effector genes that implement cellular phenotypes. Spatial mapping of cells into a cellular expression atlas, and wholemount in situ hybridization of group-specific genes reveals spatially coherent transcriptional domains in the larval body, comprising, for example, apical sensory-neurosecretory cells versus neural/epidermal surface cells. These domains represent new, basic subdivisions of the annelid body based entirely on differential gene expression, and are composed of multiple, transcriptionally similar cell types. They do not represent clonal domains, as revealed by developmental lineage analysis. We propose that the transcriptional domains that subdivide the annelid larval body represent families of related cell types that have arisen by evolutionary diversification. Their possible evolutionary conservation makes them a promising tool for evo-devo research.


Asunto(s)
Larva/citología , Larva/metabolismo , Poliquetos/citología , Poliquetos/metabolismo , Transcriptoma , Animales , Evolución Biológica , Poliquetos/crecimiento & desarrollo , Análisis de Secuencia de ARN , Análisis de la Célula Individual
9.
Methods Mol Biol ; 1649: 111-125, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29130193

RESUMEN

The method described here aims at the construction of a single-cell resolution gene expression atlas for an animal or tissue, combining in situ hybridization (ISH) and single-cell mRNA-sequencing (scRNAseq).A high resolution and medium-coverage gene expression atlas of an animal or tissue of interest can be obtained by performing a series of ISH experiments, followed by a process of image registration and gene expression averaging. Using the overlapping fraction of the genes, concomitantly obtained scRNAseq data can be fitted into the spatial context of the gene expression atlas, complementing the coverage by genes.


Asunto(s)
Regulación de la Expresión Génica , Análisis de la Célula Individual/métodos , Transcriptoma/genética , Animales , Larva/citología , Larva/genética , Programas Informáticos
10.
Proc Natl Acad Sci U S A ; 114(23): 5878-5885, 2017 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-28584082

RESUMEN

The comparative study of cell types is a powerful approach toward deciphering animal evolution. To avoid selection biases, however, comparisons ideally involve all cell types present in a multicellular organism. Here, we use image registration and a newly developed "Profiling by Signal Probability Mapping" algorithm to generate a cellular resolution 3D expression atlas for an entire animal. We investigate three-segmented young worms of the marine annelid Platynereis dumerilii, with a rich diversity of differentiated cells present in relatively low number. Starting from whole-mount expression images for close to 100 neural specification and differentiation genes, our atlas identifies and molecularly characterizes 605 bilateral pairs of neurons at specific locations in the ventral nerve cord. Among these pairs, we identify sets of neurons expressing similar combinations of transcription factors, located at spatially coherent anterior-posterior, dorsal-ventral, and medial-lateral coordinates that we interpret as cell types. Comparison with motor and interneuron types in the vertebrate neural tube indicates conserved combinations, for example, of cell types cospecified by Gata1/2/3 and Tal transcription factors. These include V2b interneurons and the central spinal fluid-contacting Kolmer-Agduhr cells in the vertebrates, and several neuron types in the intermediate ventral ganglionic mass in the annelid. We propose that Kolmer-Agduhr cell-like mechanosensory neurons formed part of the mucociliary sole in protostome-deuterostome ancestors and diversified independently into several neuron types in annelid and vertebrate descendants.


Asunto(s)
Evolución Biológica , Poliquetos/genética , Algoritmos , Animales , Tipificación del Cuerpo/genética , Diferenciación Celular , Perfilación de la Expresión Génica/métodos , Regulación del Desarrollo de la Expresión Génica , Modelos Biológicos , Neuronas/citología , Poliquetos/citología
11.
Development ; 143(23): 4495-4508, 2016 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-27789623

RESUMEN

Serotonergic and glutamatergic neurons of the dorsal raphe regulate many brain functions and are important for mental health. Their functional diversity is based on molecularly distinct subtypes; however, the development of this heterogeneity is poorly understood. We show that the ventral neuroepithelium of mouse anterior hindbrain is divided into specific subdomains giving rise to serotonergic neurons as well as other types of neurons and glia. The newly born serotonergic precursors are segregated into distinct subpopulations expressing vesicular glutamate transporter 3 (Vglut3) or serotonin transporter (Sert). These populations differ in their requirements for transcription factors Gata2 and Gata3, which are activated in the post-mitotic precursors. Gata2 operates upstream of Gata3 as a cell fate selector in both populations, whereas Gata3 is important for the differentiation of the Sert+ precursors and for the serotonergic identity of the Vglut3+ precursors. Similar to the serotonergic neurons, the Vglut3-expressing glutamatergic neurons, located in the central dorsal raphe, are derived from neural progenitors in the ventral hindbrain and express Pet1 Furthermore, both Gata2 and Gata3 are redundantly required for their differentiation. Our study demonstrates lineage relationships of the dorsal raphe neurons and suggests that functionally significant heterogeneity of these neurons is established early during their differentiation.


Asunto(s)
Núcleo Dorsal del Rafe/citología , Factor de Transcripción GATA2/genética , Factor de Transcripción GATA3/genética , Neurogénesis/genética , Rombencéfalo/embriología , Neuronas Serotoninérgicas/citología , Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Animales , Ratones , Ratones Noqueados , Células-Madre Neurales/citología , Neurogénesis/fisiología , Neuroglía/citología , Rombencéfalo/fisiología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Inhibidores de Captación de Serotonina y Norepinefrina/farmacología , Factores de Transcripción/biosíntesis
12.
Nat Biotechnol ; 33(5): 503-9, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25867922

RESUMEN

Understanding cell type identity in a multicellular organism requires the integration of gene expression profiles from individual cells with their spatial location in a particular tissue. Current technologies allow whole-transcriptome sequencing of spatially identified cells but lack the throughput needed to characterize complex tissues. Here we present a high-throughput method to identify the spatial origin of cells assayed by single-cell RNA-sequencing within a tissue of interest. Our approach is based on comparing complete, specificity-weighted mRNA profiles of a cell with positional gene expression profiles derived from a gene expression atlas. We show that this method allocates cells to precise locations in the brain of the marine annelid Platynereis dumerilii with a success rate of 81%. Our method is applicable to any system that has a reference gene expression database of sufficiently high resolution.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Poliquetos/genética , Análisis de la Célula Individual/métodos , Animales , Especificidad de Órganos/genética , Poliquetos/crecimiento & desarrollo , Transcriptoma/genética
13.
Genome Biol ; 15(10): 496, 2014 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-25418892

RESUMEN

A report on the second Single Cell Genomics conference held in Stockholm, Sweden, September 9-11, 2014.


Asunto(s)
Genómica , Proteómica/métodos , Análisis de Secuencia de ADN , Transducción de Señal , Análisis de la Célula Individual/métodos , Transcriptoma
14.
PLoS Comput Biol ; 10(9): e1003824, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25254363

RESUMEN

Complex tissues, such as the brain, are composed of multiple different cell types, each of which have distinct and important roles, for example in neural function. Moreover, it has recently been appreciated that the cells that make up these sub-cell types themselves harbour significant cell-to-cell heterogeneity, in particular at the level of gene expression. The ability to study this heterogeneity has been revolutionised by advances in experimental technology, such as Wholemount in Situ Hybridizations (WiSH) and single-cell RNA-sequencing. Consequently, it is now possible to study gene expression levels in thousands of cells from the same tissue type. After generating such data one of the key goals is to cluster the cells into groups that correspond to both known and putatively novel cell types. Whilst many clustering algorithms exist, they are typically unable to incorporate information about the spatial dependence between cells within the tissue under study. When such information exists it provides important insights that should be directly included in the clustering scheme. To this end we have developed a clustering method that uses a Hidden Markov Random Field (HMRF) model to exploit both quantitative measures of expression and spatial information. To accurately reflect the underlying biology, we extend current HMRF approaches by allowing the degree of spatial coherency to differ between clusters. We demonstrate the utility of our method using simulated data before applying it to cluster single cell gene expression data generated by applying WiSH to study expression patterns in the brain of the marine annelid Platynereis dumereilii. Our approach allows known cell types to be identified as well as revealing new, previously unexplored cell types within the brain of this important model system.


Asunto(s)
Biología Computacional/métodos , Perfilación de la Expresión Génica/métodos , Análisis de la Célula Individual/métodos , Animales , Análisis por Conglomerados , Bases de Datos Factuales , Hibridación Fluorescente in Situ , Cadenas de Markov , Poliquetos/citología , Poliquetos/metabolismo
15.
Curr Opin Genet Dev ; 27: 102-8, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24998387

RESUMEN

Cell types are composed of cellular modules exerting specific subfunctions. The evolutionary emergence and diversification of these modules can be tracked through the comparative analysis of genomes. Here, we survey recent advances elucidating the origin of neurons, of smooth and striated muscle cells and of the T- and B-cells of the immune system in the diverging lineages of animal evolution. Gene presence and absence analyses in various metazoan genomes allow mapping the step-wise assembly of key modules - such as the postsynaptic density characteristic for neurons or the z-disk characteristic for striated muscle - on the animal evolutionary tree. Using this approach, first insight into the structural evolution of cell types can be gained.


Asunto(s)
Evolución Biológica , Animales , Diferenciación Celular , Genoma , Humanos , Sistema Inmunológico , Músculo Esquelético/citología
16.
Cell Mol Life Sci ; 71(8): 1395-415, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24196748

RESUMEN

Neurons using gamma-aminobutyric acid (GABA) as their neurotransmitter are the main inhibitory neurons in the mature central nervous system (CNS) and show great variation in their form and function. GABAergic neurons are produced in all of the main domains of the CNS, where they develop from discrete regions of the neuroepithelium. Here, we review the gene expression and regulatory mechanisms controlling the main steps of GABAergic neuron development: early patterning of the proliferative neuroepithelium, production of postmitotic neural precursors, establishment of their identity and migration. By comparing the molecular regulation of these events across CNS, we broadly identify three regions utilizing distinct molecular toolkits for GABAergic fate determination: telencephalon-anterior diencephalon (DLX2 type), posterior diencephalon-midbrain (GATA2 type) and hindbrain-spinal cord (PTF1A and TAL1 types). Similarities and differences in the molecular regulatory mechanisms reveal the core determinants of a GABAergic neuron as well as provide insights into generation of the vast diversity of these neurons.


Asunto(s)
Diferenciación Celular/fisiología , Sistema Nervioso Central/embriología , Neuronas GABAérgicas/citología , Neuronas GABAérgicas/fisiología , Regulación del Desarrollo de la Expresión Génica/fisiología , Modelos Biológicos , Neurogénesis/fisiología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Tipificación del Cuerpo/fisiología , Linaje de la Célula/fisiología , Movimiento Celular/fisiología , Sistema Nervioso Central/citología , Neuronas GABAérgicas/clasificación , Regulación del Desarrollo de la Expresión Génica/genética , Humanos , Proteínas Proto-Oncogénicas/metabolismo , Proteína 1 de la Leucemia Linfocítica T Aguda , Factores de Transcripción/metabolismo
17.
Biol Open ; 2(10): 990-7, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24167708

RESUMEN

Midbrain- and hindbrain-derived GABAergic interneurons are critical for regulation of sleep, respiratory, sensory-motor and motivational processes, and they are implicated in human neurological disorders. However, the precise mechanisms that underlie generation of GABAergic neuron diversity in the midbrain-hindbrain region are poorly understood. Here, we show unique and overlapping requirements for the related bHLH proteins Tal1 and Tal2 in GABAergic neurogenesis in the midbrain. We show that Tal2 and Tal1 are specifically and sequentially activated during midbrain GABAergic neurogenesis. Similar to Gata2, a post-mitotic selector of the midbrain GABAergic neuron identity, Tal2 expression is activated very early during GABAergic neuron differentiation. Although the expression of Tal2 and Gata2 genes are independent of each other, Tal2 is important for normal midbrain GABAergic neurogenesis, possibly as a partner of Gata2. In the absence of Tal2, the majority of midbrain GABAergic neurons switch to a glutamatergic-like phenotype. In contrast, Tal1 expression is activated in a Gata2 and Tal2 dependent fashion in the more mature midbrain GABAergic neuron precursors, but Tal1 alone is not required for GABAergic neuron differentiation from the midbrain neuroepithelium. However, inactivation of both Tal2 and Tal1 in the developing midbrain suggests that the two factors co-operate to guide GABAergic neuron differentiation in a specific ventro-lateral midbrain domain. The observed similarities and differences between Tal1/Tal2 and Gata2 mutants suggest both co-operative and unique roles for these factors in determination of midbrain GABAergic neuron identities.

18.
Development ; 139(20): 3795-805, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22991444

RESUMEN

Diverse mechanisms regulate development of GABAergic neurons in different regions of the central nervous system. We have addressed the roles of a proneural gene, Ascl1, and a postmitotic selector gene, Gata2, in the differentiation of GABAergic neuron subpopulations in three diencephalic prosomeres: prethalamus (P3), thalamus (P2) and pretectum (P1). Although the different proliferative progenitor populations of GABAergic neurons commonly express Ascl1, they have distinct requirements for it in promotion of cell-cycle exit and GABAergic neuron identity. Subsequently, Gata2 is activated as postmitotic GABAergic precursors are born. In P1, Gata2 regulates the neurotransmitter identity by promoting GABAergic and inhibiting glutamatergic neuron differentiation. Interestingly, Gata2 defines instead the subtype of GABAergic neurons in the rostral thalamus (pTh-R), which is a subpopulation of P2. Without Gata2, the GABAergic precursors born in the pTh-R fail to activate subtype-specific markers, but start to express genes typical of GABAergic precursors in the neighbouring P3 domain. Thus, our results demonstrate diverse mechanisms regulating differentiation of GABAergic neuron subpopulations and suggest a role for Gata2 as a selector gene of both GABAergic neuron neurotransmitter and prosomere subtype identities in the developing diencephalon. Our results demonstrate for the first time that neuronal identities between distinct prosomeres can still be transformed in postmitotic neuronal precursors.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Diencéfalo/embriología , Neuronas GABAérgicas/metabolismo , Factor de Transcripción GATA2/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Encéfalo/embriología , Diferenciación Celular , Diencéfalo/citología , Factor de Transcripción GATA2/genética , Factor de Transcripción GATA3/biosíntesis , Factor de Transcripción GATA3/genética , Regulación del Desarrollo de la Expresión Génica , Ratones , Ratones Transgénicos , Neurogénesis , Tálamo/citología , Tálamo/embriología , Activación Transcripcional
19.
Development ; 139(13): 2360-70, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22627282

RESUMEN

GABAergic neurons in the ventral mesodiencephalic region are highly important for the function of dopaminergic pathways that regulate multiple aspects of behavior. However, development of these neurons is poorly understood. We recently showed that molecular regulation of differentiation of the GABAergic neurons associated with the dopaminergic nuclei in the ventral midbrain (VTA and SNpr) is distinct from the rest of midbrain, but the reason for this difference remained elusive. Here, we have analyzed the developmental origin of the VTA and SNpr GABAergic neurons by genetic fate mapping. We demonstrate that the majority of these GABAergic neurons originate outside the midbrain, from rhombomere 1, and move into the ventral midbrain only as postmitotic neuronal precursors. We further show that Gata2, Gata3 and Tal1 define a subpopulation of GABAergic precursors in ventral rhombomere 1. A failure in GABAergic neuron differentiation in this region correlates with loss of VTA and SNpr GABAergic neurons in Tal1 mutant mice. In contrast to midbrain, GABAergic neurons of the anterior SNpr in the diencephalon are not derived from the rhombomere 1. These results suggest unique migratory pathways for the precursors of important GABAergic neuron subpopulations, and provide the basis for understanding diversity within midbrain GABAergic neurons.


Asunto(s)
Neuronas Dopaminérgicas/fisiología , Neuronas GABAérgicas/fisiología , Sustancia Negra/crecimiento & desarrollo , Área Tegmental Ventral/crecimiento & desarrollo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/análisis , Linaje de la Célula , Movimiento Celular , Desarrollo Embrionario , Femenino , Factor de Transcripción GATA2/análisis , Factor de Transcripción GATA3/análisis , Ratones , Proteínas Proto-Oncogénicas/análisis , Sustancia Negra/citología , Proteína 1 de la Leucemia Linfocítica T Aguda , Área Tegmental Ventral/citología
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