Shed CNTNAP2 ectodomain is detectable in CSF and regulates Ca2+ homeostasis and network synchrony via PMCA2/ATP2B2

Martín-de-Saavedra, María Dolores; Santos, Marc Dos; Culotta, Lorenza; Varea, Olga; Spielman, Benjamin P.; Parnell, Euan; Forrest, Marc P.; Gao, Ruoqi; Yoon, Sehyoun; McCoig, Emmarose; Jalloul, Hiba A.; Myczek, Kristoffer; Khalatyan, Natalia; Hall, Elizabeth A.; Turk, Liam S.; Sanz-Clemente, Antonio; Comoletti, Davide; Lichtenthaler, Stefan F.; Burgdorf, Jeffrey; Barbolina, Maria V.; Savas, Jeffrey N.; Penzes, Peter

doi:10.1016/j.neuron.2021.11.025

Cited by 22 publications

(30 citation statements)

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“…This finding is especially noteworthy in light of the neuronal over-excitation frequently reported in the brains of autistic individuals (Rodenas-Cuadrado et al, 2016), and could relate to the seizures that commonly occur in individuals with CNTNAP2 loss-of-function mutations. Accordingly, the levels of the cleaved CASPR2 N-terminus are reduced in the cerebral spinal fluid of individuals with ASD, which further supports this hypothesis (Martín- de-Saavedra et al, 2022).…”

Section: The Contactin-associated Protein-like 2 Proteinsupporting

confidence: 69%

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The role of contactin-associated protein-like 2 in neurodevelopmental disease and human cerebral cortex evolution

George-Hyslop

Kivisild²,

Livesey³

2022

Front. Mol. Neurosci.

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The contactin-associated protein-like 2 (CNTNAP2) gene is associated with multiple neurodevelopmental disorders, including autism spectrum disorder (ASD), intellectual disability (ID), and specific language impairment (SLI). Experimental work has shown that CNTNAP2 is important for neuronal development and synapse formation. There is also accumulating evidence for the differential use of CNTNAP2 in the human cerebral cortex compared with other primates. Here, we review the current literature on CNTNAP2, including what is known about its expression, disease associations, and molecular/cellular functions. We also review the evidence for its role in human brain evolution, such as the presence of eight human accelerated regions (HARs) within the introns of the gene. While progress has been made in understanding the function(s) of CNTNAP2, more work is needed to clarify the precise mechanisms through which CNTNAP2 acts. Such information will be crucial for developing effective treatments for CNTNAP2 patients. It may also shed light on the longstanding question of what makes us human.

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Section: The Contactin-associated Protein-like 2 Proteinsupporting

confidence: 69%

“…Lastly, recent work has identified that synaptic potentiation triggers the N-terminal region of CASPR2 to be cleaved ( Martín-de-Saavedra et al, 2022 ). This ecto-domain localizes extracellularly near synapses, and binds and activates the PMCA calcium extrusion pump.…”

Section: Introductionmentioning

confidence: 99%

The role of contactin-associated protein-like 2 in neurodevelopmental disease and human cerebral cortex evolution

George-Hyslop

Kivisild²,

Livesey³

2022

Front. Mol. Neurosci.

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“…IQGAP1 plays a modulatory role in cytoskeleton assembly of actin ( Cheung et al, 2013 ). ATP2B2 has an active regulatory role in calcium homeostasis in neuronal systems ( Martin-De-Saavedra et al, 2022 ). Glutamate is an important excitatory neurotransmitter that together with its receptor has a regulatory role in autonomy, conductivity and self-discipline ( Hearn et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Exploration of the regulatory mechanisms of regeneration, anti-oxidation, anti-aging and the immune response at the post-molt stage of Eriocheir sinensis

Wang

et al. 2022

Front. Physiol.

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Eriocheir sinensis is widely appreciated by the surrounding population due to its culinary delicacy and rich nutrients. The E. sinensis breeding industry is very prosperous and molting is one of the important growth characteristics. Research on the regulation of molting in E. sinensis is still in the initial stages. There is currently no relevant information on the regulatory mechanisms of heart development following molting. Comparative transcriptome analysis was used to study developmental regulation mechanisms in the heart of E. sinensis at the post-molt and inter-molt stages. The results indicated that many regulatory pathways and genes involved in regeneration, anti-oxidation, anti-aging and the immune response were significantly upregulated after molting in E. sinensis. Aside from cardiac development, the differentially expressed genes (DEGs) were relevant to myocardial movement and neuronal signal transduction. DEGs were also related to the regulation of glutathione homeostasis and biological rhythms in regard to anti-oxidation and anti-aging, and to the regulation of immune cell development and the immune response. This study provides a theoretical framework for understanding the regulation of molting in E. sinensis and in other economically important crustaceans.

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“…Lentiviral vectors for expression of ARNT, mutant ARNT, or a scramble control were packaged and titrated by the Northwestern Genomic Editing and Screening Core (GET iN Core), as previously described. (Martin-de-Saavedra, Dos Santos et al 2022)…”

Section: Methodsmentioning

confidence: 99%

A Novel ARNT-Dependent HIF-2α Signaling as a Protective Mechanism for Cardiac Microvascular Barrier Integrity and Heart Function Post-Myocardial Infarction

Ullah

et al. 2023

Preprint

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Rationale: Cardiac microvascular leakage and inflammation are triggered during myocardial infarction (MI) and contribute to heart failure. Hypoxia-inducible factor 2α (Hif2α) is highly expressed in endothelial cells (ECs) and rapidly activated by myocardial ischemia, but whether it has a role in endothelial barrier function during MI is unclear. Objective: To test our hypothesis that the expression of Hif2α and its binding partner aryl hydrocarbon nuclear translocator (ARNT) in ECs regulate cardiac microvascular permeability in infarcted hearts. Methods and Results: Experiments were conducted with mice carrying an inducible EC-specific Hif2α-knockout (ecHif2α-/-) mutation, with mouse cardiac microvascular endothelial cells (CMVECs) isolated from the hearts of ecHif2α-/- mice after the mutation was induced, and with human CMVECs and umbilical-vein endothelial cells transfected with ecHif2α siRNA. After MI induction, echocardiographic assessments of cardiac function were significantly lower, while measures of cardiac microvascular leakage (Evans blue assay), plasma IL6 levels, and cardiac neutrophil accumulation and fibrosis (histology) were significantly greater, in ecHif2α-/- mice than in control mice, and RNA-sequencing analysis of heart tissues from both groups indicated that the expression of genes involved in vascular permeability and collagen synthesis was enriched in ecHif2α-/- hearts. In cultured ECs, ecHif2α deficiency was associated with declines in endothelial barrier function (electrical cell impedance assay) and the reduced abundance of tight-junction proteins, as well as an increase in the expression of inflammatory markers, all of which were largely reversed by the overexpression of ARNT. We also found that ARNT, but not Hif2α, binds directly to the IL6 promoter and suppresses IL6 expression. Conclusions: EC-specific deficiencies in Hif2α expression significantly increase cardiac microvascular permeability, promote inflammation, and reduce cardiac function in infarcted mouse hearts, and ARNT overexpression can reverse the upregulation of inflammatory genes and restore endothelial-barrier function in Hif2α-deficient ECs.

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Shed CNTNAP2 ectodomain is detectable in CSF and regulates Ca2+ homeostasis and network synchrony via PMCA2/ATP2B2

Cited by 22 publications

References 74 publications

The role of contactin-associated protein-like 2 in neurodevelopmental disease and human cerebral cortex evolution

The role of contactin-associated protein-like 2 in neurodevelopmental disease and human cerebral cortex evolution

Exploration of the regulatory mechanisms of regeneration, anti-oxidation, anti-aging and the immune response at the post-molt stage of Eriocheir sinensis

A Novel ARNT-Dependent HIF-2α Signaling as a Protective Mechanism for Cardiac Microvascular Barrier Integrity and Heart Function Post-Myocardial Infarction

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