A homeodomain protein selectively expressed in noradrenergic tissue regulates transcription of neurotransmitter biosynthetic genes

Zellmer, Eustacia; Zhang, Zheng; Greco, Dominique; Rhodes, Jennifer; Cassel, Seth H.; Lewis, Elaine J.

doi:10.1523/jneurosci.15-12-08109.1995

Cited by 101 publications

(77 citation statements)

References 53 publications

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“…Transient Transfection Assays-The DBH promoter contains three HD sites (ATTA) that interact with Arix (22,23,24) and two putative E-boxes (CANNTG), which could be potential dHAND-binding sites (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

“…Previous work has demonstrated that Arix can activate the DBH promoter by binding to three HD sites in the promoter proximal region (22,23,24). The DBH promoter also contains two putative E-boxes, and it was originally thought that dHAND could activate transcription by binding to these sites.…”

Section: Dhand Interacts Independent Of Dna Bindingmentioning

confidence: 99%

“…Moreover, when dHAND was overexpressed in avian neural crest cells, mRNAs encoding the noradrenergic biosynthetic enzymes tyrosine hydroxylase and dopamine ␤-hydroxylase (DBH) were detected, indicating a potential role of dHAND in catecholaminergic cell development. Arix regulates norepinephrine biosynthesis by directly binding to three HD sites (ATTA) in the 5Ј-upstream region of the DBH gene (22)(23)(24). The DBH promoter region also contains two putative E-box motifs (CAATTG and CAAATG), yet neither matches the dHAND consensus sequence (CATCTG) determined by the in vitro CASTing method (6).…”

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confidence: 99%

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The Interaction between dHAND and Arix at the Dopamine β-Hydroxylase Promoter Region Is Independent of Direct dHAND Binding to DNA

Rychlik

Gerbasi

Lewis

2003

Journal of Biological Chemistry

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Dopamine ␤-hydroxylase (DBH) catalyzes the production of norepinephrine, and its expression defines the noradrenergic phenotype. Transcription factors dHAND, a basic helix-loop-helix protein, and Arix/ Phox2a, a homeoprotein, have been demonstrated to play a role in the differentiation and maintenance of catecholaminergic neurons. Three Arix regulatory sites have been identified in the DBH promoter proximal region, but there is no such evidence for dHAND. Cotransfection with a DBH promoter-luciferase reporter construct plus dHAND or dHAND-E12 expression plasmids did not alter luciferase activity, whereas transfection with Arix resulted in a 2.5-fold stimulation of luciferase activity. However, a 5.5-fold increase was observed when Arix and dHAND were combined, and an 8-fold level of expression was observed when Arix was transfected with a dHAND mutant lacking the basic DNAbinding domain. When the homeodomain sites in the DBH promoter proximal region were mutated, all activity was lost, demonstrating dependence upon Arix-DNA interaction for transcriptional activation. In electrophoretic mobility shift assays, the addition of dHAND decreased the amount of Arix needed to elicit a mobility shift with the DBH homeodomain sites, and the dHAND basic mutant potentiated Arix binding in a manner similar to wild-type dHAND. The dHAND-Arix complex was dissociated upon the addition of an unlabeled competitor containing a homeodomain, but not upon the addition of a competitor containing E-boxes. Arix coprecipitated with antisera directed against recombinant dHAND, demonstrating direct protein-protein interactions. These results indicate that the activation of the DBH promoter by Arix is potentiated by dHAND via a mechanism independent of a direct interaction of dHAND with DNA.Cell-specific transcription is accomplished by the precise and transient interactions of numerous and complex molecular factors. Basic helix-loop-helix (bHLH) 1 proteins are transcription factors that play an important role in the development and differentiation of specific cell types such as neurons (1), appendages (2), and myocytes (3, 4). These bHLH proteins have been shown to bind to defined consensus sites, E-boxes (CANNTG), through the basic domain and require dimerization partners (via helices) to activate transcription. These proteins have been divided into several classes based on structure, function, and tissue specificity. Class I bHLH proteins (E12 and E47) are expressed ubiquitously in all tissues and can function as homodimers, but prefer to form heterodimers with other bHLH proteins (5). Class II proteins (dHAND, NeuroD, and MyoD) are expressed in specific tissues and are believed to be functionally active when complexed with a class I protein (5, 6). dHAND/HAND2 (deciduum, heart, autonomic nervous system, and neural crest cell derivatives) is a 30-kDa member of the class II bHLH protein family (7,8) and has been detected in Xenopus, zebrafish, chicks, mice, and humans (9). dHAND is required for cardiac (7), vascular (10), and craniofacial...

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Section: Resultsmentioning

confidence: 99%

Section: Dhand Interacts Independent Of Dna Bindingmentioning

confidence: 99%

mentioning

confidence: 99%

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The Interaction between dHAND and Arix at the Dopamine β-Hydroxylase Promoter Region Is Independent of Direct dHAND Binding to DNA

Rychlik

Gerbasi

Lewis

2003

Journal of Biological Chemistry

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“…An E-box/ dyad motif is required for the appropriate expression of a reporter gene in a catecholaminergic cell line and is potentially recognized by bHLH and zinc finger transcription factors (34,55). Several classes of homeodomain proteins may bind juxtaposed oct/hept elements (18,87). In a one-hybrid genetic screen, we used the E-box/dyad and oct/hept elements as targets to identify novel transcription factors present in the brain.…”

Section: Discussionmentioning

confidence: 99%

“…The E box may be recognized by bHLH and some zinc finger transcription factors (34,55) and is surrounded by a dyad symmetry element that could interact with other families of transcription factors. The juxtaposed oct/hept elements can bind several classes of homeodomain proteins, including POU and paired-like proteins (18,87). Two E-box/ dyad motif-interacting proteins, rITF2 and CDP2, were previously identified (85).…”

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confidence: 99%

ZENON, a Novel POZ Kruppel-Like DNA Binding Protein Associated with Differentiation and/or Survival of Late Postmitotic Neurons

Kiefer

Chatail-Hermitte

Ravassard

et al. 2005

Molecular and Cellular Biology

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The rat tyrosine hydroxylase gene promoter contains an E-box/dyad motif and an octameric and heptameric element that may be recognized by classes of transcription factors highly expressed during nervous system development. In a one-hybrid genetic screen, we used these sites as targets to isolate cDNAs encoding new transcription factors present in the brain. We identified ZENON, a novel rat POZ protein that contains two clusters of Kruppel-like zinc fingers and that presents several features of a transcription factor. ZENON is found in nuclei following transient transfection with the cDNA. The N-terminal zinc finger cluster contains a DNA binding domain that interacts with the E box. Cotranfection experiments revealed that ZENON induces tyrosine hydroxylase promoter activity. Unlike other POZ proteins, the ZENON POZ domain is not required for either activation of transcription or self-association. In the embryonic neural tube, ZENON expression is restricted to neurons that have already achieved mitosis and are engaged in late stages of neuronal differentiation (late postmitotic neurons). ZENON neuronal expression persists in the adult brain; therefore, ZENON can be considered a marker of mature neurons. We propose that ZENON is involved in the maintenance of panneuronal features and/or in the survival of mature neurons.The two major cell types in the nervous system, neurons and glia, both comprise a large number of subtypes. The generation and maintenance of this phenotypic diversity require extracellular signals that are converted into tightly regulated transcriptional cascades. Many transcription factors involved in these cascades-often basic helix-loop-helix (bHLH), homeodomain, or zinc finger-containing proteins-remain to be identified. Description of these factors would help elucidate the molecular events leading to the differentiation of the various cell types in the nervous system.One way to identify these factors is to isolate novel proteins that interact with sequences promoting the neural expression of a highly developmentally regulated gene. A good candidate is the gene encoding tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis (44, 56). The expression of the TH gene is a common feature of all neurons and neuroendocrine cells that synthesize and release catecholamines (dopamine, norepinephrine, and epinephrine). These cells are extremely diverse in their functional, morphological, and anatomical properties and have different embryonic origins. Depending on their locations in the adult central nervous system (CNS) and peripheral nervous system (PNS), catecholaminergic cells originate from different parts of the neural tube and neural crest (6,73,74). In the embryonic neural tube, catecholaminergic cell groups arise from various neuromeres (64, 78), suggesting that a large number of extracellular signals and transcription factors govern the specification and maintenance of catecholaminergic identity.The production and functional analysis of knockout mice revealed the essen...

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Engrailed protein is expressed in interneurons but not motor neurons of the dorsal unpaired median group in the adult grasshopper

Siegler

Pankhaniya

1997

J. Comp. Neurol.

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We report that the homeodomain protein Engrailed (En) is differentially expressed by neuronal type. Expression was examined within identified midline neurons in T3, A1, and A2 neuromeres of the adult grasshopper by using immunohistochemistry. All save a few neurons in the adult dorsal unpaired median (DUM) group arise embryonically from a single precursor, the median neuroblast. DUM neurons are efferent neurons, local interneurons, or intersegmental interneurons, recognizable as such by their distinct morphologies and neurotransmitter phenotypes. We show that interneurons are En-positive, whereas efferents are En-negative. In the T3 DUM group, the 70 or so interneurons contained cytoplasmic immunoreactivity for gamma-aminobutyric acid (GABA) and glutamate decarboxylase. In double-labeling experiments, all GABA-immunoreactive neurons were also En-positive, and all En-positive neurons contained GABA immunoreactivity. In complementary experiments, the 20 or so efferents in the T3 DUM group, which are octopaminergic, were selectively labeled with a histological marker and then processed to reveal En immunoreactivity. No efferents in the group were En-positive. The abdominal DUM groups contain fewer neurons, but the same dichotomy of labeling was found. The En pattern is established during embryogenesis, with the type-specific pattern apparent by stage 90% of development, the earliest stage examined here. The differential expression of En in the embryo and its continued expression in the adult nervous system suggest a role in the development and maintenance of neuronal phenotype. Morphological differences between efferents and interneurons are discussed in light of a hypothesis that En mediates differential expression of cell adhesion or cell-affinity molecules.

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A homeodomain protein selectively expressed in noradrenergic tissue regulates transcription of neurotransmitter biosynthetic genes

Cited by 101 publications

References 53 publications

The Interaction between dHAND and Arix at the Dopamine β-Hydroxylase Promoter Region Is Independent of Direct dHAND Binding to DNA

The Interaction between dHAND and Arix at the Dopamine β-Hydroxylase Promoter Region Is Independent of Direct dHAND Binding to DNA

ZENON, a Novel POZ Kruppel-Like DNA Binding Protein Associated with Differentiation and/or Survival of Late Postmitotic Neurons

Engrailed protein is expressed in interneurons but not motor neurons of the dorsal unpaired median group in the adult grasshopper

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