Cyclic AMP Signaling Functions as a Bimodal Switch in Sympathoadrenal Cell Development in Cultured Primary Neural Crest Cells

Bilodeau, Matthew L.; Boulineau, Theresa; Hullinger, Ronald L.; Andrisani, Ourania M.

doi:10.1128/mcb.20.9.3004-3014.2000

Cited by 32 publications

(51 citation statements)

References 69 publications

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“…Exposure to BMPs leads to the sequential induction of Mash1 and Phox2a/Arix expression (8,37). However, induction of TH and DBH expression in mammalian neuronal crest stem cell culture requires the activation of PKA, through the elevation of intracellular cAMP (8), and cAMP potentiates the influence of BMPs in inducing TH expression in avian neural crest cultures (38). In other developmental processes such as renal branching morphogenesis (39) and chondrogenesis (40), BMP2 has been demonstrated to increase PKA activity.…”

Section: Discussionmentioning

confidence: 99%

The Paired-like Homeodomain Protein, Arix, Mediates Protein Kinase A-stimulated Dopamine β-Hydroxylase Gene Transcription through Its Phosphorylation Status

Adachi

Lewis

2002

Journal of Biological Chemistry

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In the central and peripheral nervous systems, identity of neurotransmitter is a pivotal attribute for proper function of a neuron. Neurotransmitter phenotype is represented by the ability of a neuron to synthesize, release, and uptake the neurotransmitter. Therefore, the expression of a biosynthetic enzyme and/or vesicular transporter in its given neuron defines a neurotransmitter identity. A coordinated array of gene expression ultimately defines the phenotype of any neuron. Indeed, many transcription factors have been shown to play a key role in deciding the fate of a progenitor cell and in linking the cell to a variety of extracellular stimuli during development. Transcription factors of the homeodomain and basic-helix-loop-helix classes of proteins are frequently involved in the determination of cell type specificity (1, 2).Noradrenergic neurons are characterized by the coexpression of the catecholamine biosynthetic enzymes, tyrosine hydroxylase (TH) 1 and DBH. TH, the rate-limiting enzyme of catecholamine biosynthesis, catalyzes the production of dihydroxyphenylalanine, which is in turn converted to dopamine by amino acid decarboxylase. DBH is the terminal enzyme that produces noradrenaline from dopamine; thus, the expression of DBH is essential for determination of noradrenergic cells. For specification of noradrenergic neurons, the paired-like homeodomain transcription factors, Arix/Phox2a and NBPhox/ Phox2b, appear to act in concert to regulate noradrenergic traits in both the central and peripheral nervous systems (3). Arix and NBPhox are closely related homeodomain proteins that share significant amino acid sequence homology, including 100% identity in the homeodomain and 50% identity in the N terminus to the homeodomain. Coordinate action of Arix and NBPhox is essential for the proper development of central and peripheral noradrenergic cells. Targeted deletion analyses of Phox2a (4 -6) and Phox2b (7) demonstrate the necessity of these genes to direct noradrenergic neuronal differentiation. Despite this implication, forced expression of Phox2a is only able to induce the expression of TH but not DBH in mammalian neural crest stem cell cultures. Importantly, the expression of both TH and DBH is evoked by Phox2a only together with bone morphogenetic protein 2 (BMP2) and forskolin, which increases intracellular cAMP levels (8). In contrast, in chicken and zebrafish, forced expression of Phox2a is sufficient to promote the generation of ectopic noradrenergic neurons that express TH, DBH, and pan-neuronal genes (4, 9, 10). These experimental findings in vivo and in ovo suggest that Phox2a requires an additional factor and/or an environmental stimulus that is present in the embryo in order to potentiate activation of target genes.Phox2a expression is maintained in adult noradrenergic cells, where it likely functions to sustain the expression of the genes necessary for noradrenaline biosynthesis. The transcription of TH and DBH is regulated postnatally by environmental stimuli, such as stress, which trigger i...

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Section: Discussionmentioning

confidence: 99%

The Paired-like Homeodomain Protein, Arix, Mediates Protein Kinase A-stimulated Dopamine β-Hydroxylase Gene Transcription through Its Phosphorylation Status

Adachi

Lewis

2002

Journal of Biological Chemistry

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“…Growth Media and Other Reagents-Reagents for NC cultures were described in Bilodeau et al (16). Concentrations of other reagents used were 10 ng/ml BMP2 (Wyeth Pharmaceuticals Inc.), 100 M 3-isobutylmethylxanthine (IBMX; Sigma), 1-10 nM okadaic acid (OA; Sigma), and 5-10 M H89 (Sigma), as indicated.…”

Section: Methodsmentioning

confidence: 99%

“…Neural Crest Cell Cultures-Primary cultures of NC cells were prepared from J. quail embryos, stage 14 -15 (39), as described (16). Briefly, 48-h embryo explants from trunk region of neural tube were cultured for 42 h. After removal of neural tube (Fig.…”

Section: Methodsmentioning

confidence: 99%

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The cAMP Pathway Regulates Both Transcription and Activity of the Paired Homeobox Transcription Factor Phox2a Required for Development of Neural Crest-derived and Central Nervous System-derived Catecholaminergic Neurons

Chen

Paris

et al. 2005

Journal of Biological Chemistry

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Pluripotent neural crest (NC) cells differentiate to diverse lineages, including the neuronal, sympathoadrenal lineage. In primary NC cultures, bone morphogenetic protein 2 (BMP2) requires moderate activation of cAMP signaling for induction of the sympathoadrenal lineage. However, the mechanism by which cAMP signaling synergizes with BMP2 to induce the sympathodrenal lineage is unknown. Herein, we demonstrate that moderate activation of cAMP signaling induces both transcription and activity of proneural transcription factor Phox2a. In NC cultures inhibition of cAMPresponse element-binding protein (CREB)-mediated transcription by expression of dominant-negative CREB suppresses Phox2a transcription and sympathoadrenal lineage development. Interestingly, the constitutively active CREB DIEDML , despite inducing Phox2a transcription, is insufficient for sympathoadrenal lineage development, requiring activation of the cAMP pathway. Because CREB-DIEDML mediates cAMP-dependent transcription without requiring activation by the cAMP-dependent protein kinase A (PKA), these results identify PKA activation as necessary in sympathoadrenal lineage development. Treatment of NC cultures with the PKA inhibitor H89 or 1-10 nM okadaic acid (OA), a serine/threonine PP2A-like phosphatase inhibitor, suppresses sympathoadrenal lineage development. Likewise, OA treatment of the CNS-derived catecholaminergic CAD cell line inhibits cAMP-mediated neuronal differentiation. Specifically, OA inhibits cAMP-mediated Phox2a dephosphorylation, cAMP-dependent Phox2a DNA binding in vitro, and cAMP-and Phox2a-dependent dopamine-␤-hydroxylase-luciferase reporter expression. Together, these results support cAMP-dependent Phox2a dephosphorylation is required for its activation. We conclude that moderate activation of cAMP signaling has dual inputs in catecholaminergic, sympathoadrenal lineage development; that is, regulation of both Phox2a transcription and activity. These results provide the first mechanistic understanding of how moderate activation of the cAMP pathway in synergy with BMP2 promotes sympathoadrenal lineage development. The neural crest (NC)3 is a pluripotent cell population derived from the lateral ridges of the neuroepithelium during closure of the neural tube (1). NC cells migrate along defined paths in the developing embryo, generating diverse cell types (2). The sympathoadrenal (SA) lineage originating from the trunk region of the neural tube (1) in response to instructive, microenvironmental signals develops to sympathetic neurons and chromaffin cells of the adrenal medulla (3). Cells committed to the SA lineage are characterized by expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, and dopamine-␤-hydroxylase (DBH), catalyzing the conversion of dopamine to norepinephrine (3).Bone morphogenetic proteins (BMPs) produced by the developing aorta (4 -9) and unidentified signals originating from the notochord and ventral neural tube (10 -14) are required for SA cell development. However, in ...

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“…The discovery within the last several years that Phox2a (also called Arix), in addition to binding to the TH and DBH gene promoters (18), controls expression of the cell cycle regulator p27 kip1 (14) was of considerable interest in linking these two types of cellular events. The developmentally expressed morphogen BMP2, via induction of achaete-scute homologs (MASH in mice), and cyclic AMP (cAMP) elevation (in response to various G s -coupled first messengers) synergize to induce transcription of the Phox2a gene (2,12,14). Additional cAMP-dependent signaling is then required for the activation of Phox2a to allow its coordinated binding to the promoters of genes for chemical coding, such as the DBH gene, and those for exit from the cell cycle, such as the p27 kip1 gene.…”

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confidence: 99%

Timing the Phox-Trot: Duration of Phox2a-Dependent Transcription Is Controlled by an Intramolecular Dephosphorylation/Phosphorylation Clock

Eiden

2009

Molecular and Cellular Biology

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Cyclic AMP Signaling Functions as a Bimodal Switch in Sympathoadrenal Cell Development in Cultured Primary Neural Crest Cells

Cited by 32 publications

References 69 publications

The Paired-like Homeodomain Protein, Arix, Mediates Protein Kinase A-stimulated Dopamine β-Hydroxylase Gene Transcription through Its Phosphorylation Status

The Paired-like Homeodomain Protein, Arix, Mediates Protein Kinase A-stimulated Dopamine β-Hydroxylase Gene Transcription through Its Phosphorylation Status

The cAMP Pathway Regulates Both Transcription and Activity of the Paired Homeobox Transcription Factor Phox2a Required for Development of Neural Crest-derived and Central Nervous System-derived Catecholaminergic Neurons

Timing the Phox-Trot: Duration of Phox2a-Dependent Transcription Is Controlled by an Intramolecular Dephosphorylation/Phosphorylation Clock

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