Cleavage within Reelin Repeat 3 Regulates the Duration and Range of the Signaling Activity of Reelin Protein

Koie, Mari; Okumura, Kentaro; Hisanaga, Arisa; Kamei, Takana; Sasaki, Kazutomo; Deng, Mengyan; Baba, Atsushi; Kohno, Takao; Hattori, Mitsuharu

doi:10.1074/jbc.m113.536326

Cited by 70 publications

(51 citation statements)

References 56 publications

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“…Mock control media were collected from non-Reelin construct transfected HEK293 cells, and purified by the same method as above (Sinagra et al, 2005;Rogers et al, 2013). Reelin is cleaved extracellularly at two sites, resulting in the generation of three major fragments: the N-terminus to repeat 2 (roughly 180 kDa), the central fragment from repeat 3-6 (roughly 190 kDa), and the C-terminal fragment consisting of repeats 7 and 8 (roughly 80 kDa) (Nakajima et al, 1997;de Rouvroit et al, 1999;Utsunomiya-Tate et al, 2000;Jossin et al, 2004Jossin et al, , 2007Krstic et al, 2012;Koie et al, 2014;Trotter et al, 2014). Additionally, two intermediate fragments are produced: one consisting of the N-terminus to repeat 6 (roughly 370 kDa), and one consisting of repeats 6-8 (roughly 270 kDa) (Jossin et al, 2004).…”

Section: Reelin Purificationmentioning

confidence: 99%

Reelin supplementation recovers synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome

Hethorn

Ciarlone

Filonova

et al. 2015

Eur J of Neuroscience

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The Reelin signaling pathway is implicated in processes controlling synaptic plasticity and hippocampus-dependent learning and memory. A single direct in vivo application of Reelin enhances long-term potentiation, increases dendritic spine density and improves associative and spatial learning and memory. Angelman syndrome (AS) is a neurological disorder that presents with an overall defect in synaptic function, including decreased long-term potentiation, reduced dendritic spine density, and deficits in learning and memory, making it an attractive model in which to examine the ability of Reelin to recover synaptic function and cognitive deficits. In this study, we investigated the effects of Reelin administration on synaptic plasticity and cognitive function in a mouse model of AS and demonstrated that bilateral, intraventricular injections of Reelin recover synaptic function and corresponding hippocampus-dependent associative and spatial learning and memory. Additionally, we describe alteration of the Reelin profile in tissue from both the AS mouse and post-mortem human brain.

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Section: Reelin Purificationmentioning

confidence: 99%

Reelin supplementation recovers synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome

Hethorn

Ciarlone

Filonova

et al. 2015

Eur J of Neuroscience

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“…The N-R2 region has also been reported to bind alpha 3 beta 1 -integrins (Dulabon et al, 2000). Recently, it has been shown that reelin can be cleaved within the repeat 3 (R3) and that this produced N-terminal fragment is transported or diffuses to further regions than the larger fragments or full-length reelin (Koie et al, 2014). These results support a role of the N-terminal fragment in the range and duration of reelin signaling (Koie et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Extracellular proteolysis of reelin by tissue plasminogen activator following synaptic potentiation

Trotter

Lussier

et al. 2014

Neuroscience

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The secreted glycoprotein reelin plays an indispensable role in neuronal migration during development and in regulating adult synaptic functions. The upstream mechanisms responsible for initiating and regulating the duration and magnitude of reelin signaling are largely unknown. Here we report that reelin is cleaved between EGF-like repeats 6–7 (R6–7) by tissue plasminogen activator (tPA) under cell-free conditions. No changes were detected in the level of reelin and its fragments in the brains of tPA knockouts, implying that other unknown proteases are responsible for generating reelin fragments found constitutively in the adult brain. Induction of NMDAR-independent long-term potentiation with the potassium channel blocker tetraethylammonium chloride (TEA-Cl) led to a specific up-regulation of reelin processing at R6–7 in wild-type mice. In contrast, no changes in reelin expression and processing were observed in tPA knockouts following TEA-Cl treatment. These results demonstrate that synaptic potentiation results in tPA-dependent reelin processing and suggest that extracellular proteolysis of reelin may regulate reelin signaling in the adult brain.

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“…These fragments are likely generated by two proteolytic cleavage events, occurring between Reelin repeats (R) R2-R3, and R6-R7 (Fig. 1A), as previously described for unpurified Reelin conditioned medium (29,37,40). These cleavage events could be the result of spontaneous protein processing or they could be due to the activity of miniscule amounts of proteases that co-purify with FL Reelin.…”

Section: Expression and Purification Of Full-length Reelin And Itsmentioning

confidence: 99%

Reelin Induces Erk1/2 Signaling in Cortical Neurons Through a Non-canonical Pathway

Lee

Chhangawala

Daake

et al. 2014

Journal of Biological Chemistry

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Background: Reelin controls many aspects of brain development and function. Results: Purified Reelin activates Erk1/2 signaling and gene expression, but previously identified receptors and adaptor molecules are not required for these activities. Conclusion: Activation of Erk1/2 signaling by Reelin occurs through a novel signaling mechanism. Significance: Reelin induces Erk/1/2 signaling and thus promotes events that are required for neuronal maturation.

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Cleavage within Reelin Repeat 3 Regulates the Duration and Range of the Signaling Activity of Reelin Protein

Cited by 70 publications

References 56 publications

Reelin supplementation recovers synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome

Reelin supplementation recovers synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome

Extracellular proteolysis of reelin by tissue plasminogen activator following synaptic potentiation

Reelin Induces Erk1/2 Signaling in Cortical Neurons Through a Non-canonical Pathway

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