An NGF-TrkA-Mediated Retrograde Signal to Transcription Factor CREB in Sympathetic Neurons

Riccio, Antonella; Pierchala, Brian A.; Ciarallo, Christopher; Ginty, David D.

doi:10.1126/science.277.5329.1097

Cited by 402 publications

(285 citation statements)

References 29 publications

(3 reference statements)

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“…These signaling endosomes carry with them the machinery of the ras-raf-MAP kinase signaling cascades, and can continue to activate these pathways once inside the cell (Howe et al 2001). Neurotrophin signaling endosomes may then be retrogradely transported back to the cell body along microtubules, where they can activate transcriptional regulators and induce new gene expression (Riccio et al 1997;Watson et al 1999 In these experiments, a wall separates the culture dish into two or more compartments, and although the axons can grow under the wall into the distal compartment, the contents of the culture media do not diffuse from one side to the other. In this way, factors can be added exclusively to the axons or cell bodies to the exclusion of the other.…”

Section: Where Do Extracellular Signals Act To Induce Axon Elongation?mentioning

confidence: 99%

How does an axon grow?

Goldberg¹

2003

Genes Dev.

203

138

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How do axons grow during development, and why do they fail to regrow when injured? In the complicated mesh of our nervous system, the axon is the information superhighway, carrying all of the data we use to sense our environment and carry out behaviors. To wire up our nervous system properly, neurons must elongate their axons during development to reach their targets. This is no simple task, however. The complex morphology of axons and dendrites puts neurons among the most intricate and beautiful cells in the body. Knowledge of how neurons extend axons and dendrites, elongate at a particular rate, and stop growing at the proper time is critical to understanding the development of our nervous system, yet the regulation of these processes is poorly understood. Considerable attention in recent years has focused on understanding how growth cones are guided and steered through complicated pathways (for review, see Schmidt and Hall 1998;Mueller 1999), and even how neurons initiate new processes (for review, see Da Silva and Dotti 2002), but what mechanisms are involved in elongation itself? Are environmental signals needed to drive axon growth and, if so, what are the intracellular molecular mechanisms by which they induce elongation? What controls the rate of axon growth? How do CNS neurons know whether to extend axons or dendrites? Is the signaling of axon versus dendrite growth attributable to different extracellular signals, different neuronal states, or both? All of these questions bear critically on our understanding of axon growth and here I review recent answers and approaches to the above questions, and highlight their relevance during development, injury, and disease.

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Section: Where Do Extracellular Signals Act To Induce Axon Elongation?mentioning

confidence: 99%

How does an axon grow?

Goldberg¹

2003

Genes Dev.

203

138

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“…CREB phosphorylation may also occur downstream from NCAM-dependent autocrine GDNF-mediated signaling in SCs thus contributing to the SC proliferation observed in the compression and epineurotomy models (Iwase, et al 2005). pCREB was not colocalized to axons, but nuclear CREB phosphorylation secondary to long-range signaling through retrograde shuttling of receptor-ligand complexes was not evaluated (Riccio, et al 1997, Watson, et al 2001). …”

Section: Discussionmentioning

confidence: 98%

Axotomy or compression is required for axonal sprouting following end-to-side neurorrhaphy

Hayashi

Pannucci

Moradzadeh³

et al. 2008

Experimental Neurology

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End-to-side (ETS) nerve repair remains an area of intense scrutiny for peripheral nerve surgeonscientists. In this technique, the transected end of an injured nerve, representing the "recipient" is sutured to the side of an uninjured "donor" nerve. Some work suggests that the recipient limb is repopulated with regenerating collateral axonal sprouts from the donor nerve that go on to form functional synapses. Significant, unresolved questions include whether the donor nerve needs to be injured to facilitate regeneration, and whether a single donor neuron is capable of projecting additional axons capable of differentially innervating disparate targets. We serially imaged living transgenic mice (n=66) expressing spectral variants of GFP in various neuronal subsets after undergoing previously described atraumatic, compressive, or epineurotomy forms of ETS repair (n=22 per group). To evaluate the source, and target innervation of these regenerating axons, nerve morphometry and retrograde labeling was further supplemented by confocal microscopy as well as Western blot analysis. Either compression or epineurotomy with inevitable axotomy were required to facilitate axonal regeneration into the recipient limb. Progressively more injurious models were associated with improved recipient nerve reinnervation (epineurotomy: 184±57.6 myelinated axons; compression: 78.9±13.8; atraumatic: 0), increased Schwann cell proliferation (epineurotomy: 72.2% increase; compression: 39% increase) and cAMP response-element binding protein expression at the expense of a net deficit in donor axon counts distal to the repair. These differences were manifest by 150 days, at which point quantitative evidence for pruning was obtained. We conclude that ETS repair relies upon injury to the donor nerve.

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“…Certain cellular activities of trophic factors are known to be mediated by intracellular kinases, such as ERK, p38, and CKIV, which ultimately phosphorylate CREB. 20,56,68 However, the reduction in mRNA coding for CREB observed following injury suggests that there may be no substrate to phosphorylate. Therefore, after trauma, although levels of trophic factors and their receptors may be maintained, the intracellular signaling cascade responsible for their trophic actions may be down-regulated or impaired.…”

Section: Discussionmentioning

confidence: 99%

Traumatic injury induces differential expression of cell death genes in organotypic brain slice cultures determined by complementary DNA array hybridization

et al. 2000

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Abstract-The expression of a large panel of selected genes hypothesized to play a central role in post-traumatic cell death was shown to be differentially altered in response to a precisely controlled, mechanical injury applied to an organotypic slice culture of the rat brain. Within 48 h of injury, the expression of nerve growth factor messenger RNA was significantly increased whereas the levels of bcl-2, a-subunit of calcium/calmodulin-dependent protein kinase II, cAMP response element binding protein, 65,000 mol. wt isoform of glutamate decarboxylase, 1b isoform of protein kinase C, and ubiquitin messenger RNA were significantly decreased. Because the expression levels of a number of other messenger RNAs such as the neuron-specific amyloid precursor protein, b 2 microglobulin, bax, bcl xl , brain-derived neurotrophic factor, cyclooxygenase-2, interleukin-1b, interleukin-6, tumor necrosis factor-a, receptor tyrosine kinase A, and receptor tyrosine kinase B were unaffected, these selective changes may represent components of an active and directed response of the brain initiated by mechanical trauma.Interpretation of these co-ordinated alterations suggests that mechanical injury to the central nervous system may lead to disruption of calcium homeostasis resulting in altered gene expression, an impairment of intracellular cascades responsible for trophic factor signaling, and initiation of apoptosis via multiple pathways. An understanding of these transcriptional changes may contribute to the development of novel therapeutic strategies to enhance beneficial and blunt detrimental, endogenous, post-injury response mechanisms. ᭧ 2000 IBRO. Published by Elsevier Science Ltd.Key words: genomic expression, in vitro model, traumatic brain injury, organotypic culture, stretch injury, cDNA array.The primary mechanical event associated with traumatic injury to the CNS initiates a cascade of molecular and cellular events which include changes in gene expression, culminating in cell dysfunction and/or death. Although the initial injury occurs in less than 1 s, the post-traumatic sequelae may take hours or days to develop, thereby providing an opportunity to therapeutically attenuate detrimental or augment beneficial endogenous responses in an attempt to limit resultant cell death. A detailed analysis of these specific molecular events may aid in the rational development of novel therapies for the brain-injured patient. Many genes which have been reported to be up-regulated following experimental models of traumatic brain injury (TBI), such as c-fos, c-jun, junB or zif/ 268, 24,54,58,69 are transcription factors that control the expression of other genes, suggesting that the expression of a large number of genes, including those involved in cell death or survival, may be affected by trauma.In this regard, expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), necessary for neuronal and other cell survival, has been shown to be increased after controlled cortical impact (CCI) injury in the rat. ...

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An NGF-TrkA-Mediated Retrograde Signal to Transcription Factor CREB in Sympathetic Neurons

Cited by 402 publications

References 29 publications

How does an axon grow?

How does an axon grow?

Axotomy or compression is required for axonal sprouting following end-to-side neurorrhaphy

Traumatic injury induces differential expression of cell death genes in organotypic brain slice cultures determined by complementary DNA array hybridization

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