Large Pore Ion and Metabolite-Permeable Channel Regulation of Postnatal Ventricular Zone Neural Stem and Progenitor Cells: Interplay between Aquaporins, Connexins, and Pannexins?

The birth of new neurons from unspecialized neural stem and progenitor cells surrounding the lateral ventricles occurs throughout postnatal life. This process, termed neurogenesis, is complex and multistepped, encompassing several types of cellular behaviours, such as proliferation, differentiation, and migration. These behaviours are influenced by numerous factors present in the unique, permissive microenvironment. A major cellular mechanism for sensing the plethora of environmental cues directing this process is the presence of different channel forming proteins spanning the plasma membrane. So-called large pore membrane channels, which are selective for the passage of specific types of small molecules and ions, are emerging as an important subgroup of channel proteins. Here, we focus on the roles of three such large pore channels, aquaporin 4, connexin 43, and pannexin 1. We highlight both their independent functions as well as the accumulating evidence for crosstalk between them

Powerful partnership: crosstalk between pannexin 1 and the cytoskeleton

The roles of pannexin 1 (Panx1) large-pore ion and metabolite channels are becoming recognized in many physiological and pathophysiological scenarios. Recent evidence has tightly linked Panx1 trafficking and function to the cytoskeleton, a multi-component network that provides critical structural support, transportation, and scaffolding functions in all cell types. Here we review early work demonstrating the mechanosensitive activation of Panx1 channels, and expand on more recent evidence directly linking Panx1 to the cytoskeleton. Further, we examine the reciprocal regulation between Panx1 and the cytoskeleton, and discuss the involvement of Panx1 in cytoskeletal-regulated cell behaviors. Finally, we identify important gaps in the current knowledge surrounding this emerging Panx1-cytoskeleton relationship

Pannexin 1 regulates postnatal neural stem and progenitor cell proliferation

<p>Abstract</p> <p>Background</p> <p>Pannexin 1 forms ion and metabolite permeable hexameric channels and is abundantly expressed in the brain. After discovering pannexin 1 expression in postnatal neural stem and progenitor cells we sought to elucidate its functional role in neuronal development.</p> <p>Results</p> <p>We detected pannexin 1 in neural stem and progenitor cells <it>in vitro</it> and <it>in vivo</it>. We manipulated pannexin 1 expression and activity in Neuro2a neuroblastoma cells and primary postnatal neurosphere cultures to demonstrate that pannexin 1 regulates neural stem and progenitor cell proliferation likely through the release of adenosine triphosphate (ATP).</p> <p>Conclusions</p> <p>Permeable to ATP, a potent autocrine/paracine signaling metabolite, pannexin 1 channels are ideally suited to influence the behavior of neural stem and progenitor cells. Here we demonstrate they play a robust role in the regulation of neural stem and progenitor cell proliferation. Endogenous postnatal neural stem and progenitor cells are crucial for normal brain health, and their numbers decline with age. Furthermore, these special cells are highly responsive to neurological injury and disease, and are gaining attention as putative targets for brain repair. Therefore, understanding the fundamental role of pannexin 1 channels in neural stem and progenitor cells is of critical importance for brain health and disease.</p

Overlap in synaptic neurological condition susceptibility pathways and the neural pannexin 1 interactome revealed by bioinformatics analyses

ABSTRACTMany neurological conditions exhibit synaptic impairments, suggesting mechanistic convergence. Additionally, the pannexin 1 (PANX1) channel and signaling scaffold is linked to several of these neurological conditions and is an emerging regulator of synaptic development and plasticity; however, its synaptic pathogenic contributions are relatively unexplored. To this end, we explored connections between synaptic neurodevelopmental disorder and neurodegenerative disease susceptibility genes discovered by genome-wide association studies (GWASs), and the neural PANX1 interactome (483 proteins) identified from mouse Neuro2a (N2a) cells. To identify shared susceptibility genes, we compared synaptic suggestive GWAS candidate genes amongst autism spectrum disorders, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. To further probe PANX1 signaling pathways at the synapse, we used bioinformatics tools to identify PANX1 interactome signaling pathways and protein–protein interaction clusters. To shed light on synaptic disease mechanisms potentially linking PANX1 and these four neurological conditions, we performed additional cross-analyses between gene ontologies enriched for the PANX1 synaptic and disease-susceptibility gene sets. Finally, to explore the regional specificity of synaptic PANX1-neurological condition connections, we identified brain region-specific elevations of synaptic PANX1 interactome and GWAS candidate gene set transcripts. Our results confirm considerable overlap in risk genes for autism spectrum disorders and schizophrenia and identify potential commonalities in genetic susceptibility for neurodevelopmental disorders and neurodegenerative diseases. Our findings also pinpointed novel putative PANX1 links to synaptic disease-associated pathways, such as regulation of vesicular trafficking and proteostasis, warranting further validation

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Panx1 regulates neural stem and progenitor cell behaviours associated with cytoskeletal dynamics and interacts with multiple cytoskeletal element

Perspectives on the role of Pannexin 1 in neural precursor cell biology

We recently reported that targeted deletion of Pannexin 1 in neural precursor cells of the ventricular zone impairs the maintenance of these cells in healthy and stroke-injured brain. Here we frame this exciting new finding in the context of our previous studies on Pannexin 1 in neural precursors as well as the close relationship between Pannexin 1 and purinergic receptors established by other groups. Moreover, we identify important gaps in our understanding of Pannexin 1 in neural precursor cell biology in terms of the underlying molecular mechanisms and functional/behavioural outcomes

Pannexin 1 Differentially Affects Neural Precursor Cell Maintenance in the Ventricular Zone and Peri-Infarct Cortex

We demonstrated previously that Pannexin 1 (Panx1), an ion and metabolite channel, promotes the growth and proliferation of ventricular zone (VZ) neural precursor cells (NPCs) in vitro. To investigate its role in vivo, we used floxed Panx1 mice in combination with viruses to delete Panx1 in VZ NPCs and to track numbers of Panx1-null and Panx1-expressing VZ NPCs over time. Two days after virus injection, Panx1-null cells were less abundant than Panx1-expressing cells, suggesting that Panx1 is required for the maintenance of VZ NPCs. We also investigated the effect of Panx1 deletion in VZ NPCs after focal cortical stroke via photothrombosis. Panx1 is essential for maintaining elevated VZ NPC numbers after stroke. In contrast, Panx1-null NPCs were more abundant than Panx1-expressing NPCs in the peri-infarct cortex. Together, these findings suggest that Panx1 plays an important role in NPC maintenance in the VZ niche in the naive and stroke brain and could be a key target for improving NPC survival in the peri-infarct cortex. Here, we demonstrate that Pannexin 1 (Panx1) maintains a consistent population size of neural precursor cells in the ventricular zone, both in the healthy brain and in the context of stroke. In contrast, Panx1 appears to be detrimental to the survival of neural precursor cells that surround damaged cortical tissue in the stroke brain. This suggests that targeting Panx1 in the peri-infarct cortex, in combination with other therapies, could improve cell survival around the injury site