Enhanced CREB phosphorylation in immature dentate gyrus granule cells precedes neurotrophin expression and indicates a specific role of CREB in granule cell differentiation.

R A Bender,J C Lauterborn,W Cariaga,T Z Baram,C M Gall

doi:10.1046/j.1460-9568.2001.01432.x

R A Bender, J C Lauterborn + Show 3 more

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Differentiation and maturation of dentate gyrus granule cells requires coordinated interactions of numerous processes. These must be regulated by protein factors capable of integrating signals mediated through diverse signalling pathways. Such integrators of inter and intracellular physiological stimuli include the cAMP-response element binding protein (CREB), a leucine-zipper class transcription factor that is activated through phosphorylation. Neuronal activity and neurotrophic factors, known to be involved in granule cell differentiation, are major physiologic regulators of CREB function. To examine whether CREB may play a role in governing coordinated gene transcription during granule cell differentiation, we determined the spatial and temporal profiles of phosphorylated (activated) CREB throughout postnatal development in immature rat hippocampus. We demonstrate that CREB activation is confined to discrete, early stages of granule cell differentiation. In addition, CREB phosphorylation occurs prior to expression of the neurotrophins BDNF and NT-3. These data indicate that in a signal transduction cascade connecting CREB and neurotrophins in the process of granule cell maturation, CREB is located upstream of neurotrophins. Importantly, CREB may be a critical component of the machinery regulating the coordinated transcription of genes contributing to the differentiation of granule cells and their integration into the dentate gyrus network.

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In most regions of mammalian brain, production of neurons is largely confined to discrete developmental periods, and the differentiation of precursors to postmitotic neurons is completed by birth
This pattern was quite different during the second postnatal week, when pCREBimmunoreactivity was drastically reduced in the pyramidal cell layer while the granule cells (GCs) layer labelling was increased (Fig 1B and C)
Immunoreactive cells were not distributed throughout the GC layer: nuclei located in the deeper half of the layer were strongly immunoreactive for phosphorylated isoform of CREB (pCREB), but immunoreactivity decreased with increasing distance from the hilus, so that GCs in the superficial half were virtually unlabeled (Figs 1C and 2A)

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In most regions of mammalian brain, production of neurons is largely confined to discrete developmental periods, and the differentiation of precursors to postmitotic neurons is completed by birth. In the dentate gyrus (DG) of the hippocampal formation, neuronal stem cells located at the inner border of the granule cell layer (the subgranular zone) continue to produce new granule cells (GCs) throughout adult life. This special quality of DG (Altman & Das, 1965; Kaplan & Hinds, 1977; Bayer et al, 1982), has attracted considerable interest because of its potential implications for brain repair. Both inter and intracellular communication is required to activate and coordinate the GC differentiation program

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