Mechanisms of splicing-dependent trans-synaptic adhesion by PTPδ–IL1RAPL1/IL-1RAcP for synaptic differentiation

Yamagata, Atsushi; Yoshida, Tomoyuki; Sato, Yusuke; Goto-Ito, Sakurako; Uemura, Takeshi; Maeda, Atsuko; Shiroshima, Tomoko; Iwasawa-Okamoto, Shiho; Mori, Hisashi; Mishina, Masayoshi; Fukai, Shuya

doi:10.1038/ncomms7926

Cited by 59 publications

(77 citation statements)

References 40 publications

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“…This binding again depends on PTPRD miniexon splicing. Crystallography confirms complexes between PTPRD immunoglobulin domains and the immunoglobulin domains of IL1RAPL1 and IL1RAP, again in a miniexon‐dependent fashion …”

Section: What Is Ptprd?mentioning

confidence: 76%

PTPRD: neurobiology, genetics, and initial pharmacology of a pleiotropic contributor to brain phenotypes

Uhl

Martínez

2019

Annals of the New York Academy of Sciences

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Receptor‐type protein tyrosine phosphatase, receptor type D (PTPRD) has likely roles as a neuronal cell adhesion molecule and synaptic specifier. Interest in its neurobiology and genomics has been stimulated by results from human genetics and mouse models for phenotypes related to addiction, restless leg syndrome, neurofibrillary pathology in Alzheimer's disease, cognitive impairment/intellectual disability, mood lability, and obsessive‐compulsive disorder. We review PTPRD's discovery, gene family, candidate homomeric and heteromeric binding partners, phosphatase activities, brain distribution, human genetic associations with nervous system phenotypes, and mouse model data relevant to these phenotypes. We discuss the recently reported discovery of the first small molecule inhibitor of PTPRD phosphatase, the identification of its addiction‐related effects, and the implications of these findings for the PTPRD‐associated brain phenotypes. In assembling PTPRD neurobiology, human genetics, and mouse genetic and pharmacological datasets, we provide a compelling picture of the roles played by PTPRD, its variation, and its potential as a target for novel therapeutics.

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Section: What Is Ptprd?mentioning

confidence: 76%

PTPRD: neurobiology, genetics, and initial pharmacology of a pleiotropic contributor to brain phenotypes

Uhl

Martínez

2019

Annals of the New York Academy of Sciences

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“…The presence of intra-synaptic IL-1β increases the ratio of synaptic AcP/AcPb adaptor proteins and decreases synaptic plasticity (Prieto et al, 2015). Decreased synaptic stability as a result of a higher AcP/AcPb ratio may be a direct consequence of AcP having a lower affinity for presynaptic PTPδ than AcPb (Yamagata et al, 2015). Therefore, binding of IL-1β to neuronal IL-1R may alter synaptic activity and prevent neurite outgrowth by disrupting the number or equilibrium of intra-synaptic cellular adhesion proteins.…”

Section: Nlrp3 Inflammasome Cytokines and Their Effectsmentioning

confidence: 99%

Principles of inflammasome priming and inhibition: Implications for psychiatric disorders

Herman

Pasinetti

2018

Brain, Behavior, and Immunity

100

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The production of inflammatory proteins by the innate immune system is a tightly orchestrated procedure that allows the body to efficiently respond to exogenous and endogenous threats. Recently, accumulating evidence has indicated that disturbances in the inflammatory response system not only provoke autoimmune disorders, but also can have deleterious effects on neuronal function and mental health. As inflammation in the brain is primarily mediated by microglia, there has been an expanding focus on the mechanisms through which these cells initiate and propagate neuroinflammation. Microglia can enter persistently active states upon their initial recognition of an environmental stressor and are thereafter prone to elicit amplified and persistent inflammatory responses following subsequent exposures to stressors. A recent focus on why primed microglia cells are susceptible to environmental insults has been the NLRP3 inflammasome. Its function within the innate immune system is regulated in such a manner that supports a role for the complex in gating neuroinflammatory responses. The activation of NLRP3 inflammasome in microglia results in the cleavage of zymogen inflammatory interleukins into functional forms that elicit a number of consequential effects in the local neuronal environment. There is evidence to support the principle that within primed neuroimmune systems a lowered threshold for NLRP3 activation can cause persistent neuroinflammation or the amplified production of inflammatory cytokines, such as IL-1β and IL-18. Over the course of an individual's lifetime, persistent neuroinflammation can subsequently lead to the pathophysiological signatures that define psychological disorders. Therefore, targeting the NLRP3 inflammasome complex may represent an innovative and consequential approach to limit neuroinflammatory states in psychiatric disorders, such as major depressive disorder.

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“…For example, the type IIa RPTPs subfamily of proteins undergoes tissue-specific alternative splicing that determines the inclusion of four short-peptide inserts, known as mini-exon peptides (meA-meD) (Pulido et al, 1995a(Pulido et al, , 1995bTakahashi and Craig, 2013) . While meB comprises four residues (ELRE) and is encoded by a single microexon, meA has three possible variants that can form as a result of the combinatorial inclusion of two microexons; meA3 (ESI), meA6 (GGTPIR) and meA9 (ESIGGTPIR) (Yamagata et al, 2015a) . Our analysis shows a consistent inclusion of meB in both GABA-ergic and glutamatergic neurons.…”

Section: Cell Type Specific Microexon Inclusion In Mouse Visual Cortexmentioning

confidence: 99%

MicroExonator enables systematic discovery and quantification of microexons across mouse embryonic development

Parada

Munita

Georgakopoulos-Soares

et al. 2020

Preprint

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Microexons, exons that are ≤30 nucleotides, were shown to play key roles in neuronal development, but are difficult to detect and quantify using standard RNA-Seq alignment tools. Here, we present MicroExonator, a novel pipeline for reproducible de novo discovery and quantification of microexons. We processed 289 RNA-seq datasets from eighteen mouse tissues corresponding to nine embryonic and postnatal stages, providing the most comprehensive survey of microexons available for mouse. We detected 2,984 microexons, 332 of which are differentially spliced throughout mouse embryonic brain development, including 29 that are not present in mouse transcript annotation databases. Unsupervised clustering of microexons alone segregates brain tissues by developmental time and further analysis suggest a key function for microexon inclusion in axon growth and synapse formation. Finally, we analysed single-cell RNA-seq data from the mouse visual cortex and we report differential inclusion between neuronal subpopulations, suggesting that some microexons could be cell-type specific. Keywords microexons, splicing, alternative splicing, neuronal development, single-cell, reproducible software we found 10 microexon clusters that did not have strong tissue-specific patterns, but were instead either constitutively included (I) or excluded (E) ( Fig 4C).

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Mechanisms of splicing-dependent trans-synaptic adhesion by PTPδ–IL1RAPL1/IL-1RAcP for synaptic differentiation

Cited by 59 publications

References 40 publications

PTPRD: neurobiology, genetics, and initial pharmacology of a pleiotropic contributor to brain phenotypes

PTPRD: neurobiology, genetics, and initial pharmacology of a pleiotropic contributor to brain phenotypes

Principles of inflammasome priming and inhibition: Implications for psychiatric disorders

MicroExonator enables systematic discovery and quantification of microexons across mouse embryonic development

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