The p75 Neurotrophin Receptor Negatively Modulates Dendrite Complexity and Spine Density in Hippocampal Neurons

Zagrebelsky, Marta; Holz, Andreas; Dechant, Georg; Barde, Yves‐Alain; Bonhoeffer, Tobias; Körte, Martin

doi:10.1523/jneurosci.2492-05.2005

Cited by 260 publications

(260 citation statements)

References 62 publications

(86 reference statements)

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“…The mouse full-length p75 NTR cDNA [GenBank accession no. BC038365 (11)] was inserted into pSP70 vector (Promega).…”

Section: Methodsmentioning

confidence: 99%

“…We used a loss-of-function approach inducing RNAimediated knockdown of PFN2a in hippocampal neurons. Furthermore, we investigated whether PFN2a might be involved in the regulation of actin dynamics downstream of known effectors of neuronal morphology, such as the pan-neurotrophin receptor p75 (p75 NTR ) in the adult nervous system (10,11). We found that on knockdown of PFN2a, the number of both dendrites and spines is significantly reduced in hippocampal pyramidal neurons.…”

mentioning

confidence: 99%

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Fine-tuning of neuronal architecture requires two profilin isoforms

Michaelsen

Murk

Zagrebelsky

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Two profilin isoforms (PFN1 and PFN2a) are expressed in the mammalian brain. Although profilins are essential for regulating actin dynamics in general, the specific role of these isoforms in neurons has remained elusive. We show that knockdown of the neuron-specific PFN2a results in a significant reduction in dendrite complexity and spine numbers of hippocampal neurons. Overexpression of PFN1 in PFN2a-deficient neurons prevents the loss of spines but does not restore dendritic complexity. Furthermore, we show that profilins are involved in differentially regulating actin dynamics downstream of the pan-neurotrophin receptor (p75 NTR ), a receptor engaged in modulating neuronal morphology. Overexpression of PFN2a restores the morphological changes in dendrites caused by p75 NTR overexpression, whereas PFN1 restores the normal spine density. Our data assign specific functions to the two PFN isoforms, possibly attributable to different affinities for potent effectors also involved in actin dynamics, and suggest that they are important for the signal-dependent finetuning of neuronal architecture.N euronal plasticity depends on functional changes at synapses and, additionally, on the spatial and temporal modulation of neuronal architecture, which is induced by the transmission of external signals to the cytoskeleton. Among the proteins engaged in the organization of the actin cytoskeleton are profilins (1) that bind to monomeric actin, polyproline-stretch proteins, and membranebound phospholipids (reviewed in ref.2). In the mammalian brain, two different profilin isoforms are found: profilin 1 (PFN1), which is ubiquitously expressed in all eukaryotic cells, and profilin 2a (PFN2a), which is tissue-restricted and shows its highest expression level in the brain (3, 4). The cell-and tissue-specific role of profilins remains poorly understood. In particular, the precise function of neuronal PFN2a is still unclear. Recent evidence points to pre-and postsynaptic functions of both isoforms. Experiments with cultured hippocampal neurons revealed activity-dependent targeting of PFN1 (5) and PFN2a (6) into spines of excitatory neurons. Furthermore, Lamprecht et al. (7) demonstrated a stimulus-dependent accumulation of profilin, without isoform specification, in spines of neurons in the rat amygdala. In addition, NMDA receptor activation was seen to correlate with changes in spine morphology, a process apparently involving PFN2a, RhoA, and the RhoA-specific kinase ROCK (8). In contrast, data derived from a KO mouse indicate that PFN2a acts presynaptically, by controlling vesicle exocytosis and presynaptic excitability (9). The aim of the current study was to unravel the physiological role of PFN2a in regulating dendrite morphology and spine stability of mature pyramidal neurons. We used a loss-of-function approach inducing RNAimediated knockdown of PFN2a in hippocampal neurons. Furthermore, we investigated whether PFN2a might be involved in the regulation of actin dynamics downstream of known effectors of neuronal morphology, su...

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“…The mouse full-length p75 NTR cDNA [GenBank accession no. BC038365 (11)] was inserted into pSP70 vector (Promega).…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Fine-tuning of neuronal architecture requires two profilin isoforms

Michaelsen

Murk

Zagrebelsky

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Neuronal morphology, as measured by dendrite arborization and spine density, is modulated by a number of extracellular signals (i.e., neurotrophins, neurotransmitters) (Horch and Katz 2002;Zagrebelsky et al 2005), and signaling via the ERK/MAPK pathway appears to function as a key conduit by which these extracellular cues influence neuronal morphology (Vaillant et al 2002;Goldin and Segal 2003;Kumar et al 2005). Interestingly, ERK/ MAPK signaling has been implicated in both transcriptionally dependent and independent forms of structural plasticity (Dijkhuizen and Ghosh 2005).…”

Section: Msk/mapk and Neuronal Morphologymentioning

confidence: 99%

MSK1 regulates environmental enrichment-induced hippocampal plasticity and cognitive enhancement

et al. 2012

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Environmental enrichment (EE) has marked beneficial effects on cognitive capacity. Given the possibility that this form of neuronal plasticity could function via the actuation of the same cellular signaling pathways that underlie learning/memory formation, we examined whether the MAPK cascade effector, mitogen/stress-activated kinase 1 (MSK1), could play a role in this process. MSK1 functions as a key signaling intermediate that couples changes in neuronal activity into inducible gene expression, neuronal plasticity, and learning/memory. Here, we show that MSK1 is expressed in excitatory cell layers of the hippocampus, progenitor cells of the subgranular zone (SGZ), and adult-born immature neurons. MSK1 2/2 mice exhibit reduced spinogenesis and decreased dendritic branching complexity in hippocampal neurons, compared with WT mice. Further, in MSK1 2/2 mice, progenitor cell proliferation within the SGZ was significantly reduced and, correspondingly, the number of immature neurons within the dentate gyrus was significantly reduced. Consistent with prior work, MSK1 2/2 mice displayed deficits in both spatial and recognition memory tasks. Strikingly, cognitive enhancement resulting from a 40-d period of EE was markedly reduced in MSK1 2/2 animals. MSK1 2/2 mice exhibited reduced levels of EE-induced spinogenesis and SGZ progenitor proliferation. Taken together, these data reveal that MSK1 serves as a critical regulator of hippocampal physiology and function and that MSK1 serves as a key conduit by which enriching stimuli augment cellular plasticity and cognition.

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“…Survival and proliferation of cortical astrocytes (Sibilia et al 1998;Wagner et al 2006); Astrocyte development and neuronal survival (Kornblum et al 1998 Regulation of neural tube development (Deng et al 1997;Hasegawa et al 2004); OL differentiation (Zhou et al 2006) p75NTR Negative regulation of hippocampal pyramidal neuron dendritic morphology and neurite outgrowth (Zagrebelsky et al 2005); Schwann cell migration, remyelination (Bentley and Lee 2000;Song et al 2006;Tomita et al 2007) TrkA Development of sensory sympathetic and cholinergic neurons Fagan et al 1996) TrkB Development of motor and/or sensory neurons (Ernfors et al 1994;Klein 1994;Pinon et al 1996); Interneuron migration (Polleux et al 2002) TrkC Development of sensory neurons Liebl et al 1997) 1998; Hirota et al 2004), in which cytoplasmic domains of the receptor are no longer accessible to signaling proteins, rendering the receptor signaling incompetent. Moreover, the increasingly acidic lysosomal environment ( pH 4.0) promotes protein degradation.…”

Section: Endocytosis and Endosomal Targetingmentioning

confidence: 99%

Directing traffic in neural cells: determinants of receptor tyrosine kinase localization and cellular responses

Romanelli

Wood²

2008

Journal of Neurochemistry

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The trafficking of receptor tyrosine kinases (RTKs) to distinct subcellular locations is essential for the specificity and fidelity of signal transduction and biological responses. This is particularly important in the PNS and CNS in which RTKs mediate key events in the development and maintenance of neurons and glia through a wide range of neural processes, including survival, proliferation, differentiation, neurite outgrowth, and synaptogenesis. The mechanisms that regulate the targeting of RTKs to their subcellular destinations for appropriate signal transduction, however, are still elusive. In this review, we discuss evidence for the spatial organization of signaling machinery into distinct subcellular compartments, as well as the role for ligand specificity, receptor sorting signals, and lipid raft microdomains in RTK targeting and the resultant cellular responses in neural cells.

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The p75 Neurotrophin Receptor Negatively Modulates Dendrite Complexity and Spine Density in Hippocampal Neurons

Cited by 260 publications

References 62 publications

Fine-tuning of neuronal architecture requires two profilin isoforms

Fine-tuning of neuronal architecture requires two profilin isoforms

MSK1 regulates environmental enrichment-induced hippocampal plasticity and cognitive enhancement

Directing traffic in neural cells: determinants of receptor tyrosine kinase localization and cellular responses

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