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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    • "All experiments were conducted using separate cohorts of male and female animals, which originated from our own transgenic mouse colonies maintained in the C57BL/6N background. Transgenic animals with selective ablation of GR in the noradrenergic system (GR DBHCre ) were obtained by crossing animals that hosted Cre recombinase under the dopamine beta-hydroxylase (DBH) promoter with animals that harbored a floxed GR gene as previously described (Parlato et al., 2007, 2009). The animals were maintained with their control (Cre-negative ) littermates of the same sex in self-ventilated cages under standard laboratory conditions (12 h light/dark cycle, food and water ad libitum) until 12 weeks of age. "
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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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    • "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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