Extracellular matrix protein reelin regulate dendritic spine density through CaMKIIβ

Kim, Mi‐Hyun; Jeong, Yun Ha; Chang, Young‐Chae

doi:10.1016/j.neulet.2015.05.033

Cited by 16 publications

(11 citation statements)

References 28 publications

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“…Dab1 conditional knockout in adult mice results in a reduced size of dendritic spines [ 208 ]. Other molecules such as CamKII (Ca2+/calmodulin-dependent protein kinase II) might also be required to enable Reelin and VLDLR to alter dendritic spine density [ 209 , 210 ].…”

Section: Reelin Signaling and Synaptic Plasticitymentioning

confidence: 99%

Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation

2020

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During embryonic development and adulthood, Reelin exerts several important functions in the brain including the regulation of neuronal migration, dendritic growth and branching, dendritic spine formation, synaptogenesis and synaptic plasticity. As a consequence, the Reelin signaling pathway has been associated with several human brain disorders such as lissencephaly, autism, schizophrenia, bipolar disorder, depression, mental retardation, Alzheimer’s disease and epilepsy. Several elements of the signaling pathway are known. Core components, such as the Reelin receptors very low-density lipoprotein receptor (VLDLR) and Apolipoprotein E receptor 2 (ApoER2), Src family kinases Src and Fyn, and the intracellular adaptor Disabled-1 (Dab1), are common to most but not all Reelin functions. Other downstream effectors are, on the other hand, more specific to defined tasks. Reelin is a large extracellular protein, and some aspects of the signal are regulated by its processing into smaller fragments. Rather than being inhibitory, the processing at two major sites seems to be fulfilling important physiological functions. In this review, I describe the various cellular events regulated by Reelin and attempt to explain the current knowledge on the mechanisms of action. After discussing the shared and distinct elements of the Reelin signaling pathway involved in neuronal migration, dendritic growth, spine development and synaptic plasticity, I briefly outline the data revealing the importance of Reelin in human brain disorders.

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Section: Reelin Signaling and Synaptic Plasticitymentioning

confidence: 99%

Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation

2020

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“…Reelin signaling also promotes dendritic spine formation and growth in the cortex and hippocampus of juvenile mice (Niu et al, 2008 ; Pujadas et al, 2010 ; Iafrati et al, 2014 ). The signaling mechanism that underlies this function involves the canonical pathway and possibly additional signaling molecules such as RasGRF1/CamMKII (DiBattista et al, 2015 ; Kim et al, 2015 ). Finally, the molecular composition of the dendritic spines is affected by Reelin.…”

Section: Reelin Signal Transduction In the Control Of Dendrite And Spmentioning

confidence: 99%

New Insights into Reelin-Mediated Signaling Pathways

Lee

D’Arcangelo

2016

Front. Cell. Neurosci.

131

111

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Reelin, a multifunctional extracellular protein that is important for mammalian brain development and function, is secreted by different cell types in the prenatal or postnatal brain. The spatiotemporal regulation of Reelin expression and distribution during development relates to its multifaceted function in the brain. Prenatally Reelin controls neuronal radial migration and proper positioning in cortical layers, whereas postnatally Reelin promotes neuronal maturation, synaptic formation and plasticity. The molecular mechanisms underlying the distinct biological functions of Reelin during and after brain development involve unique and overlapping signaling pathways that are activated following Reelin binding to its cell surface receptors. Distinct Reelin ligand isoforms, such as the full-length protein or fragments generated by proteolytic cleavage differentially affect the activity of downstream signaling pathways. In this review, we discuss recent advances in our understanding of the signaling transduction pathways activated by Reelin that regulate different aspects of brain development and function. A core signaling machinery, including ApoER2/VLDLR receptors, Src/Fyn kinases, and the adaptor protein Dab1, participates in all known aspects of Reelin biology. However, distinct downstream mechanisms, such as the Crk/Rap1 pathway and cell adhesion molecules, play crucial roles in the control of neuronal migration, whereas the PI3K/Akt/mTOR pathway appears to be more important for dendrite and spine development. Finally, the NMDA receptor (NMDAR) and an unidentified receptor contribute to the activation of the MEK/Erk1/2 pathway leading to the upregulation of genes involved in synaptic plasticity and learning. This knowledge may provide new insight into neurodevelopmental or neurodegenerative disorders that are associated with Reelin dysfunction.

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“…Reelin has been previously reported to induce tyrosine phosphorylation of the cytoplasmic NMDAR subunit NR2B through SRC family kinases, thus increasing ion conductance at the synapse and ultimately LTP . This enhanced ion conductance of synaptic NMDARs results in greater calcium influx which, in turn, results in enhanced dendritic spine density and development through Calcium/calmodulin-dependent protein kinase type II  (CaMKII) kinase activity and transcriptional activity of cAMP-response element binding protein (CREBP) Kim et al, 2015). It would be interesting to address whether Csmd2 is required for this plasticity in synaptic physiology induced by Reelin; in particular, whether the Csmd2-Dab1 interaction mediates downstream CaMKII and CREBP signaling.…”

Section: Discussionmentioning

confidence: 99%

“…The Reelin signaling pathway plays a significant role in the elaboration of the neuronal dendritic arbor and development of postsynaptic dendritic spines (Niu et al, 2004;Jossin and Goffinet, 2007;Niu et al, 2008;Chai et al, 2015;Kim et al, 2015). Supplementation of Reelin has also been shown to enhance the structural development of neurons in these contexts (Niu et al, 2004;Niu et al, 2008;Rogers et al, 2011;Rogers et al, 2013), resulting in enhanced dendritic branching and outgrowth, increased dendritic spine density, and increased long-term potentiation.…”

Section: Csmd2 Is Required For Reelin-mediated Neuronal Structural Dementioning

confidence: 99%

Csmd2 interacts with Dab1 and is Required in Reelin-Mediated Neuronal Maturation

Gutierrez

Dwyer

Franco

2020

Preprint

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Reelin is a glycoprotein secreted by Cajal-Retzius cells to regulate development of the cerebral cortex. Reelin binding to its receptors on immature neurons initiates a signaling cascade through the downstream adaptor protein, Dab1. Defects in this signaling mechanism result in perturbed neuronal migration, reductions in dendrite complexity, and deficits in synapse development and function. How Reelin controls neuronal migration and brain lamination have been extensively investigated over the years, but the pathways that regulate dendrite and spine development downstream of Reelin and Dab1 have yet to be fully elucidated. Here, we have identified a novel interaction between Dab1 and Csmd2, a synaptic transmembrane protein required for dendrite and dendritic spine development in forebrain excitatory neurons. We demonstrate that Csmd2 contains an NPxY motif on its intracellular region, through which Dab1 interacts with Csmd2. Interestingly, we find that this NPxY consensus motif is not required for Csmd2 to localize at the postsynaptic densities of spiny neurons. Rather, the introduction of an NPxY mutant form of Csmd2 results in a significant overproduction of immature, filopodia-like dendritic spines in maturing neurons. Moreover, we show that knockdown of Csmd2 mRNA expression in immature developing neurons abolishes the ability of Reelin to promote dendrite elaboration and dendritic spine maturation. This suggests that the Csmd2-Dab1 interaction may be a requirement of Reelin/Dab1 signaling to mediate the structural maturation of neurons. Together, these results point toward a role of Csmd2 in the Reelin/Dab1 signaling axis that promotes the development of dendrites and dendritic spines in maturing neurons.Summary StatementHow Reelin controls neuronal maturation remains to be understood. We demonstrate that the synaptic protein Csmd2 interacts with the Reelin-associated adaptor protein Dab1. We also determine that Reelin requires Csmd2 to regulate structural development and maturation of forebrain neurons.

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Extracellular matrix protein reelin regulate dendritic spine density through CaMKIIβ

Cited by 16 publications

References 28 publications

Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation

Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation

New Insights into Reelin-Mediated Signaling Pathways

Csmd2 interacts with Dab1 and is Required in Reelin-Mediated Neuronal Maturation

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