Specific ablation of the transcription factor CREB in sympathetic neurons surprisingly protects against developmentally regulated apoptosis

Division of Molecular Biology of the Cell II , German Cancer Research Center, Heidelburg, Baden-Württemberg, Germany
Development (Impact Factor: 6.46). 06/2007; 134(9):1663-70. DOI: 10.1242/dev.02838
Source: PubMed


The cyclic-AMP response element-binding (CREB) protein family of transcription factors plays a crucial role in supporting the survival of neurons. However, a cell-autonomous role has not been addressed in vivo. To investigate the cell-specific role of CREB, we used as a model developing sympathetic neurons, whose survival in vitro is dependent on CREB activity. We generated mice lacking CREB in noradrenergic (NA) and adrenergic neurons and compared them with the phenotype of the germline CREB mutant. Whereas the germline CREB mutant revealed increased apoptosis of NA neurons and misplacement of sympathetic precursors, the NA neuron-specific mutation unexpectedly led to reduced levels of caspase-3-dependent apoptosis in sympathetic ganglia during the period of naturally occurring neuronal death. A reduced level of p75 neurotrophin receptor expression in the absence of CREB was shown to be responsible. Thus, our analysis indicates that the activity of cell-autonomous pro-survival signalling is operative in developing sympathetic neurons in the absence of CREB.

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Available from: Rosanna Parlato, Oct 06, 2015
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    • "Conserved features of gene expression during neuronal development are the delayed induction of Syt1 as compared to neurofilament expression during early differentiation stages [15] as well as the slow increase in synaptic protein mRNA levels during advanced stages of neuronal development. To search for evidence of microRNA-mediated regulation in these processes, Dicer 1 was conditionally inactivated by DBH promoter-driven Cre recombinase [50-52]. "
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    ABSTRACT: Neurons in sympathetic ganglia and neuroendocrine cells in the adrenal medulla share not only their embryonic origin from sympathoadrenal precursors in the neural crest but also a range of functional features. These include the capacity for noradrenaline biosynthesis, vesicular storage and regulated release. Yet the regulation of neuronal properties in early neuroendocrine differentiation is a matter of debate and the developmental expression of the vesicle fusion machinery, which includes components found in both neurons and neuroendocrine cells, is not resolved. Analysis of synaptic protein and pan-neuronal marker mRNA expression during mouse development uncovers profound differences between sympathetic neurons and adrenal chromaffin cells, which result in qualitatively similar but quantitatively divergent transcript profiles. In sympathetic neurons embryonic upregulation of synaptic protein mRNA follows early and persistent induction of pan-neuronal marker transcripts. In adrenal chromaffin cells pan-neuronal marker expression occurs only transiently and synaptic protein messages remain at distinctly low levels throughout embryogenesis. Embryonic induction of synaptotagmin I (Syt1) in sympathetic ganglia and postnatal upregulation of synaptotagmin VII (Syt7) in adrenal medulla results in a cell type-specific difference in isoform prevalence. Dicer 1 inactivation in catecholaminergic cells reduces high neuronal synaptic protein mRNA levels but not their neuroendocrine low level expression. Pan-neuronal marker mRNAs are induced in chromaffin cells to yield a more neuron-like transcript pattern, while ultrastructure is not altered. Our study demonstrates that remarkably different gene regulatory programs govern the expression of synaptic proteins in the neuronal and neuroendocrine branch of the sympathoadrenal system. They result in overlapping but quantitatively divergent transcript profiles. Dicer 1-dependent regulation is required to establish high neuronal mRNA levels for synaptic proteins and to maintain repression of neurofilament messages in neuroendocrine cells.
    Neural Development 08/2013; 8(1):16. DOI:10.1186/1749-8104-8-16 · 3.45 Impact Factor
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    • "Selective ablation of GRs in the noradrenergic system (GRDBHCre mice) was achieved using the Cre/loxP approach. Transgenic mice hosting Cre recombinase under the dopamine beta-hydroxylase (DBH) promoter were crossed with animals harboring the floxed GR gene as described previously [12]. Previous studies performed on GRDBHCre mice revealed the crucial role of GRs in postnatal maintenance of chromaffin cells, resulting in the inhibition of adrenaline synthesis [13]. "
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    ABSTRACT: The aim of this study was to investigate whether conditional inactivation of the glucocorticoid receptors (GRs) in noradrenergic neurons affects animal behavior in mice. Selective ablation of GRs in the noradrenergic system was achieved using the Cre/loxP approach. We crossed transgenic mice expressing the Cre recombinase under the dopamine beta-hydroxylase (DBH) promoter with animals harboring the floxed GR gene. The resulting GR(DBHCre) mutant mice exhibited no alterations in terms of normal cage behavior, weight gain, spatial memory or spontaneous locomotor activity, regardless of gender. To assess depressive- and anxiety-like behaviors we performed the Tail Suspension Test and the Light-Dark Box Test. While male mutant animals did not show any alternations in both tests, female GR(DBHCre) mutants displayed depressive- and anxiety-like behavior. Additionally, male GR(DBHCre) mice were exposed to chronic restraint stress but still exhibited immobility times and anxiety statuses similar to those of non-stressed animals while stressed control mice clearly revealed depressive- and anxiety-like phenotype. Thus, in males the effects of the mutation were precipitated only after chronic restraint stress procedure. Our data reveal a possible gender-dependent role of GRs in the noradrenergic system in anxiety- and depressive-like behavior in mice.
    PLoS ONE 08/2013; 8(8):e72632. DOI:10.1371/journal.pone.0072632 · 3.23 Impact Factor
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    • "regions for the mouse DBH gene using a PAC harbouring the mouse DBH locus (RPCI-21 PAC mouse genomic library; Parlato et al., 2007) as template. The whole recombination cassette was transferred into the temperature-sensitive shuttle vector pSV1. "
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    ABSTRACT: We generated transgenic mice bearing a tamoxifen-dependent Cre recombinase expressed under the control of the dopamine-β-hydroxylase promoter. By crossing to the ROSA26 reporter mice we show that tamoxifen-induced Cre recombinase in adult mice specifically activates β-galactosidase expression in differentiated noradrenergic neurons of the central and peripheral nervous system. Tamoxifen application in adult mice did not induce β-galactosidase activity in parasympathetic neurons that transiently express DBH during development. Thus, this transgenic mouse line represents a valuable tool to study gene function in mature noradrenergic neurons by conditional inactivation.
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