Autoregulation and multiple enhancers control Math1 expression in the developing nervous system

Development ◽  
2000 ◽  
Vol 127 (6) ◽  
pp. 1185-1196 ◽  
Author(s):  
A.W. Helms ◽  
A.L. Abney ◽  
N. Ben-Arie ◽  
H.Y. Zoghbi ◽  
J.E. Johnson
Keyword(s):  
Nervous System ◽  
Transgenic Mice ◽  
Neural Tube ◽  
Hair Cells ◽  
Neuronal Cell ◽  
Cell Types ◽  
Regulatory Elements ◽  
Coding Region ◽  
Consensus Binding Site ◽  
Auditory Systems

Development of the vertebrate nervous system requires the actions of transcription factors that establish regional domains of gene expression, which results in the generation of diverse neuronal cell types. MATH1, a transcription factor of the bHLH class, is expressed during development of the nervous system in multiple neuronal domains, including the dorsal neural tube, the EGL of the cerebellum and the hair cells of the vestibular and auditory systems. MATH1 is essential for proper development of the granular layer of the cerebellum and the hair cells of the cochlear and vestibular systems, as shown in mice carrying a targeted disruption of Math1. Previously, we showed that 21 kb of sequence flanking the Math1-coding region is sufficient for Math1 expression in transgenic mice. Here we identify two discrete sequences within the 21 kb region that are conserved between mouse and human, and are sufficient for driving a lacZ reporter gene in these domains of Math1 expression in transgenic mice. The two identified enhancers, while dissimilar in sequence, appear to have redundant activities in the different Math1 expression domains except the spinal neural tube. The regulatory mechanisms for each of the diverse Math1 expression domains are tightly linked, as separable regulatory elements for any given domain of Math1 expression were not found, suggesting that a common regulatory mechanism controls these apparently unrelated domains of expression. In addition, we demonstrate a role for autoregulation in controlling the activity of the Math1 enhancer, through an essential E-box consensus binding site.

scholarly journals Distinct regulatory elements direct Delta1 expression in the nervous system and paraxial mesoderm of transgenic mice

2000 ◽  
Vol 95 (1-2) ◽  
pp. 23-34 ◽  
Author(s):  
Johannes Beckers ◽  
Alicia Caron ◽  
Martin Hrabé de Angelis ◽  
Stefan Hans ◽  
José A. Campos-Ortega ◽  
...  
Keyword(s):  
Nervous System ◽  
Transgenic Mice ◽  
Regulatory Elements ◽  
Paraxial Mesoderm

Clinical relevance of the neurotrophins and their receptors

2006 ◽  
Vol 110 (2) ◽  
pp. 175-191 ◽  
Author(s):  
Shelley J. Allen ◽  
David Dawbarn
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nervous System ◽  
Peripheral Nervous System ◽  
Disease Process ◽  
Neuronal Cell ◽  
Cell Types ◽  
Dependent Manner ◽  
Disease States ◽  
Neuronal Tissues

The neurotrophins are growth factors required by discrete neuronal cell types for survival and maintenance, with a broad range of activities in the central and peripheral nervous system in the developing and adult mammal. This review examines their role in diverse disease states, including Alzheimer's disease, depression, pain and asthma. In addition, the role of BDNF (brain-derived neurotrophic factor) in synaptic plasticity and memory formation is discussed. Unlike the other neurotrophins, BDNF is secreted in an activity-dependent manner that allows the highly controlled release required for synaptic regulation. Evidence is discussed which shows that sequestration of NGF (nerve growth factor) is able to reverse symptoms of inflammatory pain and asthma in animal models. Both pain and asthma show an underlying pathophysiology linked to increases in endogenous NGF and subsequent NGF-dependent increase in BDNF. Conversely, in Alzheimer's disease, there is a role for NGF in the treatment of the disease and a recent clinical trial has shown benefit from its exogenous application. In addition, reductions in BDNF, and changes in the processing and usage of NGF, are evident and it is possible that both NGF and BDNF play a part in the aetiology of the disease process. This highly selective choice of functions and disease states related to neurotrophin function, although in no way comprehensive, illustrates the importance of the neurotrophins in the brain, the peripheral nervous system and in non-neuronal tissues. Ways in which the neurotrophins, their receptors or agonists/antagonists may act therapeutically are discussed.

Functional morphology of the platyhelminth nervous system

Parasitology ◽  
1996 ◽  
Vol 113 (S1) ◽  
pp. S47-S72 ◽  
Author(s):  
D. W. Halton ◽  
M. K. S. Gustafsson
Keyword(s):  
Nervous System ◽  
Sense Organ ◽  
Neuronal Cell ◽  
Cell Types ◽  
Target Cells ◽  
Life Styles ◽  
Wide Range ◽  
Paracrine Secretion ◽  
Nervous System Evolution ◽  
Neuronal Vesicles

SUMMARYAs the most primitive metazoan phylum, the Platyhelminthes occupies a unique position in nervous system evolution. Centrally, their nervous system consists of an archaic brain from which emanate one or more pairs of longitudinal nerve cords connected by commissures; peripherally, a diverse arrangement of nerve plexuses of varying complexity innervate the subsurface epithelial and muscle layers, and in the parasitic taxa they are most prominent in the musculature of the attachment organs and egg-forming apparatus. There is a range of neuronal-cell types, the majority being multi- and bipolar. The flatworm neuron is highly secretory and contains a heterogeneity of vesicular inclusions, dominated by densecored vesicles, whose contents may be released synaptically or by paracrine secretion for presumed delivery to target cells via the extracellular matrix. A wide range of sense organ types is present in flatworms, irrespective of life-styles. The repertoire of neuronal substances identified cytochemically includes all of the major candidate transmitters known in vertebrates. Two groups of native flatworm neuropeptides have been sequenced, neuropeptide F and FMRFamide-related peptides (FaRPs), and immunoreactivities for these have been localised in dense-cored neuronal vesicles in representatives of all major fiatworm groups. There is evidence of co-localisation of peptidergic and cholinergic elements; serotoninergic components generally occupy a separate set of neurons. The actions of neuronal substances in flatworms are largely undetermined, but FaRPs and 5-HT are known to be myoactive in all of the major groups, and there is immuno-cytochemical evidence that they have a role in the mechanism of egg assembly.

scholarly journals Analyses of temporal regulatory elements of the prosaposin gene in transgenic mice

2003 ◽  
Vol 370 (2) ◽  
pp. 557-566 ◽  
Author(s):  
Ying SUN ◽  
David P. WITTE ◽  
Peng JIN ◽  
Gregory A. GRABOWSKI
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
Transgenic Mice ◽  
Peak Level ◽  
Regulatory Elements ◽  
Low Level ◽  
The Central Nervous System ◽  
Flanking Region ◽  
The Brain

The expression of prosaposin is temporally and spatially regulated at transcriptional and post-translational levels. Transgenic mice with various 5′-flanking deletions of the prosaposin promoter fused to luciferase (LUC) reporters were used to define its temporal regulatory region. LUC expression in the transgenic mice carrying constructs with 234bp (234LUC), 310bp (310LUC) or 2400bp (2400LUC) of the 5′-flanking region was analysed in the central nervous system and eye throughout development. For 310LUC and 2400LUC, low-level LUC activity was maintained until embryonal day 18 in brain, eye and spinal cord. The peak level of LUC activity was at birth, with return to a plateau (1/3 of peak) throughout adulthood. Deletion of the region that included the retinoic acid-receptor-related orphan receptor (RORα)-binding site and sequence-specific transcription factor (Sp1) cluster sites (44—310bp) suppressed the peak of activity. By comparison, the peak level for 234LUC was shifted 2 weeks into neonatal life in the brain, but not in the eye, and no peak of activity was observed in the spinal cord. The endogenous prosaposin mRNA in eye, spinal cord and cerebellum had low-level expression before birth and continued to increase into adulthood. In cerebrum, the endogenous mRNA showed similar expression profile to constructs 310LUC, 2400LUC and 234LUC, with the peak expression at 1 week and a decreased level in adult. In the brain of the newborn, 2400LUC was highly expressed in the trigeminal ganglion and brain stem regions when compared with the generalized expression pattern for endogenous prosaposin mRNA. These results suggest that the modifiers (RORα- and Sp1-binding sites) residing within 310bp of the 5′-flanking region mediate developmental regulation in the central nervous system and eye. Additional regulatory elements outside the 5′ region of the 2400bp promoter fragment appear to be essential for the physiological control of the prosaposin locus.

scholarly journals Modeling the causal regulatory network by integrating chromatin accessibility and transcriptome data

2016 ◽  
Vol 3 (2) ◽  
pp. 240-251 ◽  
Author(s):  
Yong Wang ◽  
Rui Jiang ◽  
Wing Hung Wong
Keyword(s):  
Rna Polymerase Ii ◽  
Transcript Abundance ◽  
Cell Types ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Coding Region ◽  
Regulatory Relationship ◽  
Dna Loop ◽  
Exciting Opportunity ◽  
Rich Data

Abstract Cell packs a lot of genetic and regulatory information through a structure known as chromatin, i.e. DNA is wrapped around histone proteins and is tightly packed in a remarkable way. To express a gene in a specific coding region, the chromatin would open up and DNA loop may be formed by interacting enhancers and promoters. Furthermore, the mediator and cohesion complexes, sequence-specific transcription factors, and RNA polymerase II are recruited and work together to elaborately regulate the expression level. It is in pressing need to understand how the information, about when, where, and to what degree genes should be expressed, is embedded into chromatin structure and gene regulatory elements. Thanks to large consortia such as Encyclopedia of DNA Elements (ENCODE) and Roadmap Epigenomic projects, extensive data on chromatin accessibility and transcript abundance are available across many tissues and cell types. This rich data offer an exciting opportunity to model the causal regulatory relationship. Here, we will review the current experimental approaches, foundational data, computational problems, interpretive frameworks, and integrative models that will enable the accurate interpretation of regulatory landscape. Particularly, we will discuss the efforts to organize, analyze, model, and integrate the DNA accessibility data, transcriptional data, and functional genomic regions together. We believe that these efforts will eventually help us understand the information flow within the cell and will influence research directions across many fields.

Flatworm nerve–muscle: structural and functional analysis

2004 ◽  
Vol 82 (2) ◽  
pp. 316-333 ◽  
Author(s):  
D W Halton ◽  
A G Maule
Keyword(s):  
Nervous System ◽  
Second Messengers ◽  
Signal Transduction Pathway ◽  
Neuronal Cell ◽  
Cell Types ◽  
Confocal Imaging ◽  
Muscle Fibres ◽  
Messenger Molecules ◽  
Baseline Information ◽  
Nerve Muscle

Platyhelminthes occupy a unique position in nerve–muscle evolution, being the most primitive of metazoan phyla. Essentially, their nervous system consists of an archaic brain and associated pairs of longitudinal nerve cords cross-linked as an orthogon by transverse commissures. Confocal imaging reveals that these central nervous system elements are in continuity with an array of peripheral nerve plexuses which innervate a well-differentiated grid work of somatic muscle as well as a complexity of myofibres associated with organs of attachment, feeding, and reproduction. Electrophysiological studies of flatworm muscles have exposed a diversity of voltage-activated ion channels that influence muscle contractile events. Neuronal cell types are mainly multi- and bi-polar and highly secretory in nature, producing a heterogeneity of vesicular inclusions whose contents have been identified cytochemically to include all three major types of cholinergic, aminergic, and peptidergic messenger molecules. A landmark discovery in flatworm neuro biology was the biochemical isolation and amino acid sequencing of two groups of native neuropeptides: neuro peptide F and FMRFamide-related peptides (FaRPs). Both families of neuropeptide are abundant and broadly distributed in platyhelminths, occurring in neuronal vesicles in representatives of all major flatworm taxa. Dual localization studies have revealed that peptidergic and cholinergic substances occupy neuronal sets separate from those of serotoninergic components. The physiological actions of neuronal messengers in flatworms are beginning to be established, and where examined, FaRPs and 5-HT are myoexcitatory, while cholinomimetic substances are generally inhibitory. There is immunocytochemical evidence that FaRPs and 5-HT have a regulatory role in the mechanism of egg assembly. Use of muscle strips and (or) muscle fibres from free-living and parasitic flatworms has provided baseline information to indicate that muscle responses to FaRPs are mediated by a G-protein-coupled receptor, and that the signal transduction pathway for contraction involves the second messengers cAMP and protein kinase C.

scholarly journals An integrated transcriptomic and epigenomic atlas of mouse primary motor cortex cell types

2020 ◽  
Author(s):  
Zizhen Yao ◽  
Hanqing Liu ◽  
Fangming Xie ◽  
Stephan Fischer ◽  
A. Sina Booeshaghi ◽  
...  
Keyword(s):  
Motor Cortex ◽  
Single Cell ◽  
Primary Motor Cortex ◽  
Neuronal Cell ◽  
Cell Types ◽  
Regulatory Elements ◽  
Brain Cell ◽  
Molecular Signatures ◽  
Sequencing Technologies ◽  
Cell Transcriptome

AbstractSingle cell transcriptomics has transformed the characterization of brain cell identity by providing quantitative molecular signatures for large, unbiased samples of brain cell populations. With the proliferation of taxonomies based on individual datasets, a major challenge is to integrate and validate results toward defining biologically meaningful cell types. We used a battery of single-cell transcriptome and epigenome measurements generated by the BRAIN Initiative Cell Census Network (BICCN) to comprehensively assess the molecular signatures of cell types in the mouse primary motor cortex (MOp). We further developed computational and statistical methods to integrate these multimodal data and quantitatively validate the reproducibility of the cell types. The reference atlas, based on more than 600,000 high quality single-cell or -nucleus samples assayed by six molecular modalities, is a comprehensive molecular account of the diverse neuronal and non-neuronal cell types in MOp. Collectively, our study indicates that the mouse primary motor cortex contains over 55 neuronal cell types that are highly replicable across analysis methods, sequencing technologies, and modalities. We find many concordant multimodal markers for each cell type, as well as thousands of genes and gene regulatory elements with discrepant transcriptomic and epigenomic signatures. These data highlight the complex molecular regulation of brain cell types and will directly enable design of reagents to target specific MOp cell types for functional analysis.

scholarly journals The Transcriptional Logic of Mammalian Neuronal Diversity

2017 ◽  
Author(s):  
Ken Sugino ◽  
Erin Clark ◽  
Anton Schulmann ◽  
Yasuyuki Shima ◽  
Lihua Wang ◽  
...  
Keyword(s):  
Nervous System ◽  
Signal To Noise Ratio ◽  
Cell Types ◽  
Regulatory Elements ◽  
Mobile Elements ◽  
Neuronal Diversity ◽  
Evolutionary Force ◽  
Neuronal Genes ◽  
Interspersed Repeats ◽  
Long Genes

AbstractThe mammalian nervous system is constructed of many cell types, but the principles underlying this diversity are poorly understood. To assess brain-wide transcriptional diversity, we sequenced the transcriptomes of the largest collection of genetically and anatomically identified neuronal classes. Using improved expression metrics that distinguish information content from signal-to-noise-ratio, we found that homeobox transcription factors contain the highest information about cell types and have the lowest noise. Genes that contribute the most to neuronal diversity tend to be long and enriched in factors specifically involved in neuronal function. Genome accessibility measurements reveal that long genes have more candidate regulatory elements arrayed in more distinct patterns. These elements frequently overlap interspersed repeats (mobile elements) and the pattern of repeats is predictive of gene expression. New regulatory sites resulting from elongation of neuronal genes by mobile elements may be an evolutionary force enhancing nervous system complexity.

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