Synapsin III Acts Downstream of Semaphorin 3A/CDK5 Signaling to Regulate Radial Migration and Orientation of Pyramidal Neurons In Vivo

Perlini, Laura E.; Szczurkowska, Joanna; Ballif, Bryan A.; Piccini, Alessandra; Sacchetti, Silvio; Giovedì, Silvia; Benfenati, Fabio; Cancedda, Laura

doi:10.1016/j.celrep.2015.03.022

Cited by 25 publications

(29 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…During these phases of development, the expression of isoforms derived from each synapsin gene varies. In accord with previous studies (Lohmann et al ., ; Porton et al ., ; Perlini et al ., ), synapsins I and II are expressed later in development (P7 to adulthood), while the peak of synapsin III expression occurs between P1‐P7 (Fig. E).…”

Section: Resultsmentioning

confidence: 91%

Synapsins regulate brain‐derived neurotrophic factor‐mediated synaptic potentiation and axon elongation by acting on membrane rafts

Kao

Ryoo

Lin

et al. 2017

Eur J of Neuroscience

View full text Add to dashboard Cite

In neurons, intracellular membrane rafts are essential for specific actions of brain-derived neurotrophic factor (BDNF), which include the regulation of axon outgrowth, growth cone turning and synaptic transmission. Virtually all the actions of BDNF are mediated by binding to its receptor, TrkB. The association of TrkB with the tyrosine kinase, Fyn, is critical for its localization to intracellular membrane rafts. Here, we show that synapsins, a family of highly amphipathic neuronal phosphoproteins, regulate membrane raft lipid composition and consequently, the ability of BDNF to regulate axon/neurite development and potentiate synaptic transmission. In the brains of mice lacking all synapsins, the expression of both BDNF and TrkB were increased, suggesting that BDNF/TrkB-mediated signaling is impaired. Consistent with this finding, synapsin-depleted neurons exhibit altered raft lipid composition, deficient targeting of Fyn to rafts, attenuated TrkB activation, and abrogation of BDNF-stimulated axon outgrowth and synaptic potentiation. Conversely, overexpression of synapsins in neuroblastoma cells results in corresponding reciprocal changes in raft lipid composition, increased localization of Fyn to rafts, and promotion of BDNF-stimulated neurite formation. In the presence of synapsins, the ratio of cholesterol to estimated total phospholipids converged to 1, suggesting that synapsins act by regulating the ratio of lipids in intracellular membranes, thereby promoting lipid raft formation. These studies reveal a mechanistic link between BDNF and synapsins, impacting early development and synaptic transmission.

show abstract

Section: Resultsmentioning

confidence: 91%

Synapsins regulate brain‐derived neurotrophic factor‐mediated synaptic potentiation and axon elongation by acting on membrane rafts

Kao

Ryoo

Lin

et al. 2017

Eur J of Neuroscience

View full text Add to dashboard Cite

show abstract

“…In untreated cells, filopodia number was inversely correlated to axonal nestin levels ( Figure 4G). After a low dose of Sema3a treatment (1nM for 5 minutes) (Perlini et al 2015), nestin-positive cells retracted growth cone filopodia significantly, whereas nestin-negative growth cones were not significantly affected by Sema3a during the 5 minute timeframe (shown in Figure 4B, quantified in Figure 4G). Area of the growth cone was not significantly altered in this short time frame as expected (Dent 2004), so we relied on the retraction of filopodia as our most sensitive measurement of Sema3a sensitivity.…”

Section: Nestin Protein Is Transiently Expressed Broadly Among Corticmentioning

confidence: 93%

“…Sema3a is upstream of cdk5 in neurons (Kobayashi et al 2014), and we thus utilized an in vitro bath application "Sema3a collapse assay" to test this idea. In cultured neurons, phosphorylation of cdk5 substrates and morphological changes in growth cones (Perlini et al 2015;Dent 2004) start within minutes of Sema3a exposure with the loss of growth cone filopodia, resulting ultimately in a collapsed growth cones with no filopodia. However, prior to complete growth cone collapse, Sema3a leads to retraction of individual filopodia (Dent 2004).…”

Section: Nestin Protein Is Transiently Expressed Broadly Among Corticmentioning

confidence: 99%

“…Addition of Sema3a to cortical neuron cultures causes rapid filopodial retraction (within 5 minutes) and ultimately collapse of many axonal growth cones (Dent, E W. 2004). Binding of Sema3a to its receptor neuropilin1 and coreceptor PlexinA leads to downstream activation of the neuronal serine/threonine kinase cyclin dependent kinase 5 (cdk5) (Sasaki et al 2002;Perlini et al 2015;Chen et al 2008). Cdk5 is critical for early neuronal development as a regulator of cytoskeleton, trafficking, and membrane dynamics and, thus, cell morphology (Kawauchi 2014).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Nestin in immature embryonic neurons regulates axon growth cone morphology and Semaphorin3a sensitivity

Bott

Johnson

Yap

et al. 2017

Preprint

View full text Add to dashboard Cite

Nestin is an atypical intermediate filament expressed highly in neural progenitors and is thus used widely as a progenitor marker. Nestin, but not other intermediate filament subtypes, interacts with and regulates cdk5 kinase. Here we surprisingly identify a subpopulation of embryonic cortical neurons which transiently express nestin in their axonal growth cones. Since the repulsive guidance cue Semaphorin 3a (Sema3a) activates cdk5, we tested if nestin-expressing neurons showed altered responses to Sema3a. We find that nestin-expressing neurons are more sensitive to Sema3a, and that nestin knockdown results in lowered sensitivity to Sema3a. We propose that nestin is a modulator of cdk5 in immature neurons leading to an altered Sema3a response. Since correct wiring in the neocortex requires that responses to an individual guidance cue vary among neurons in the same location, and within the same neuron over time, the transient expression of nestin could allow for temporal modulation of a neuron's response to Sema3a, critical for early cortical axon guidance decisions.peer-reviewed)

show abstract

“…5) [81]. Similarly, another study revealed that semaphorin-3A (Sema3A)-induced activation of Cdk5 causes it to phosphorylate synapsin III, which regulates radial migration and orientation in vivo [83] (Fig. 5).…”

Section: Other Cdk5 Substrates Involved In Actin Dynamics (Talin Drementioning

confidence: 99%

Tale of the Good and the Bad Cdk5: Remodeling of the Actin Cytoskeleton in the Brain

Shah

Rossie

2017

Mol Neurobiol

View full text Add to dashboard Cite

Cdk5 kinase, a cyclin-dependent kinase family member, is a key regulator of cytoskeletal remodeling in the brain. Cdk5 is essential for brain development during embryogenesis. After birth, it is essential for numerous neuronal processes such as learning and memory formation, drug addiction, pain signaling, and long-term behavior changes, all of which rely on rapid alterations in the cytoskeleton. Cdk5 activity is deregulated in various brain disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and ischemic stroke, resulting in profound remodeling of the neuronal cytoskeleton, loss of synapses, and ultimately neurodegeneration. This review focuses on the "good and bad" Cdk5 in the brain and its pleiotropic contribution in regulating neuronal actin cytoskeletal remodeling. A vast majority of physiological and pathological Cdk5 substrates are associated with the actin cytoskeleton. Thus, our special emphasis is on the numerous Cdk5 substrates identified in the past two decades such as ephexin1, p27, Mst3, CaMKv, kalirin-7, RasGRF2, Pak1, WAVE1, neurabin-1, TrkB, 5-HT6R, talin, drebrin, synapsin I, synapsin III, CRMP1, GKAP, SPAR, PSD-95, and LRRK2. These substrates have unraveled the molecular mechanisms by which Cdk5 plays divergent roles in regulating neuronal actin cytoskeletal dynamics both in healthy and diseased states.

show abstract

Synapsin III Acts Downstream of Semaphorin 3A/CDK5 Signaling to Regulate Radial Migration and Orientation of Pyramidal Neurons In Vivo

Cited by 25 publications

References 55 publications

Synapsins regulate brain‐derived neurotrophic factor‐mediated synaptic potentiation and axon elongation by acting on membrane rafts

Synapsins regulate brain‐derived neurotrophic factor‐mediated synaptic potentiation and axon elongation by acting on membrane rafts

Nestin in immature embryonic neurons regulates axon growth cone morphology and Semaphorin3a sensitivity

Tale of the Good and the Bad Cdk5: Remodeling of the Actin Cytoskeleton in the Brain

Contact Info

Product

Resources

About