Epithelial Sodium Channel Regulates Adult Neural Stem Cell Proliferation in a Flow-Dependent Manner
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One hallmark of adult neurogenesis is its adaptability to environmental influences. Here, we uncovered the epithelial sodium channel (ENaC) as a key regulator of adult neurogenesis as its deletion in neural stem cells (NSCs) and their progeny in the murine subependymal zone (SEZ) strongly impairs their proliferation and neurogenic output in the olfactory bulb. Importantly, alteration of fluid flow promotes proliferation of SEZ cells in an ENaC-dependent manner, eliciting sodium and calcium signals that regulate proliferation via calcium-release-activated channels and phosphorylation of ERK. Flow-induced calcium signals are restricted to NSCs in contact with the ventricular fluid, thereby providing a highly specific mechanism to regulate NSC behavior at this special interface with the cerebrospinal fluid. Thus, ENaC plays a central role in regulating adult neurogenesis, and among multiple modes of ENaC function, flow-induced changes in sodium signals are critical for NSC biology.
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RNA-binding proteins balance brain function in health and disease
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Self-citationCurrent Understanding of the Neural Stem Cell Niches
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Bioelectrical approaches to cancer as a problem of the scaling of the cellular self
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“…Colak et al , 2008), and ephrins (Conover et al , 2000; Nomura et al , 2010) with only few regulating the maintenance of qNSCs in the SEZ, such as PEDF (Ramirez-Castillejo et al , 2006) or components of the cerebrospinal fluid (Codega et al , 2014; Silva-Vargas et al , 2016; Petrik et al , 2018).”
Self-citationDevelopment of a straight vertebrate body axis
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L-type voltage-gated Ca2+ channel CaV1.2 regulates chondrogenesis during limb development
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“Indeed, depolarization appears to be crucial for chondrocyte differentiation as the pharmacological inhibition of ENaC, a channel known to modulate membrane depolarization in other contexts (9, 37), blocked cartilage formation in micromass cultures, and Ca transients activated by depolarization are themselves required…”
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Pathophysiology of Lipid Droplets in Neuroglia
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Does ENaC Work as Sodium Taste Receptor in Humans?
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“Recent findings indicate that ENaC plays a key role in the regulation of adult neurogenesis [54].”
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Planques, A., Moreira, V. O., Dubreuil, C., Prochiantz, A., & Nardo, A. A. D. (2019) · eNeuro · doi:10.1523/eneuro.0262-18.2019 · Cited by 57 · see citing works
Mechanobiology of neural development
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“Neural Progenitor Differentiation The neural tube is composed of radial glial cells (RGCs), a class of NSPCs.”
BackgroundInfluentialMechanical Forces Orchestrate Brain Development
Javier‐Torrent, M., Zimmer‐Bensch, G., & Nguyen, L. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.10.012 · Cited by 51 · see citing works
Choroid Plexus: The Orchestrator of Long-Range Signalling Within the CNS
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“In addition to its role as a vehicle for distribution of bioactive molecules, hydrodynamic forces associated with CSF flow establish instructive cues that are able to activate ion channels expressed by adult neural stem cells (NSCs) in direct contact with CSF, which can act as mechanosensory receptors, regulating adul…”
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Sodium Fluctuations in Astroglia and Their Potential Impact on Astrocyte Function
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Self-citationEpendymal ciliary motion and their role in congenital hydrocephalus
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Channeling Force in the Brain: Mechanosensitive Ion Channels Choreograph Mechanics and Malignancies
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Endogenous neural precursor cells in health and disease
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Ion Channels in Cancer: Orchestrators of Electrical Signaling and Cellular Crosstalk
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“In adult mouse neural stem cells of the subependymal zone, fl ow-sensitive sodium channel ENaC senses ventricular fl uid fl ow to promote proliferation and neurogenic output through Na + and Ca 2+ signaling, activation of calcium-release activated channels, and ERK signaling (Petrik et al. 2018).”
BackgroundThe origin of saltiness: oral detection of NaCl
Bigiani, A. (2020) · Current Opinion in Physiology · doi:10.1016/j.cophys.2020.11.006 · Cited by 27 · see citing works
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“The time-lapse imaging of adult neural stem cells was based on previously described protocol (Ortega et al., 2013; Petrik et al., 2018).”
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“It has also been shown that the flow of the CSF generated by the choroid plexus and ependymal cells regulates both proliferation NSCs and directional migration of their neuronal progeny in the VZ–SVZ niche (Petrik et al., 2018; Sawamoto et al., 2006).”
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Go with the Flow: Cerebrospinal Fluid Flow Regulates Neural Stem Cell Proliferation
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Cumulative Damage: Cell Death in Posthemorrhagic Hydrocephalus of Prematurity
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The δ subunit of epithelial sodium channel in humans—a potential player in vascular physiology
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Proliferative regulation of alveolar epithelial type 2 progenitor cells by human Scnn1d gene
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“ENaC is expressed in pulmonary epithelial stem and progenitor cells and implicated in the repair of injured epithelial and other tissues [40-44].”
BackgroundAdult Neurogenesis of Teleost Fish Determines High Neuronal Plasticity and Regeneration
Pushchina, E. V., Kapustyanov, I. A., & Kluka, G. G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25073658 · Cited by 16 · see citing works
“Overall, it appears that quiescence in the adult zebrafish brain is an important way to maintain the proliferative capacity of neural stem cells throughout life, as has also been shown for the mouse brain [110–112].”
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“In neural stem cells, conditional deletion of ENaCs results in the absence of inward sodium flow, which induces hyperpolarization and reduces the number and proliferation of cells in the subependymal zone (46).”
BackgroundOne progenitor to generate them all: new evidence for multi-fated neural progenitors
Álvarez, G., & Spassky, N. (2020) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2020.10.013 · Cited by 15 · see citing works
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The Neural Stem Cell Properties of PKD2L1+ Cerebrospinal Fluid-Contacting Neurons in vitro
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Calcium Channels in Adult Brain Neural Stem Cells and in Glioblastoma Stem Cells
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“Specifically, the authors of that study reported that the epithelium sodium channel (ENaC) that is located in the primary cilium of NSCs acts as a mechanosensor and requires a subsequent SOCE to control cell proliferation in V-SVZ in response to cerebrospinal fluid flow (Petrik et al., 2018).”
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“Furthermore, a study demonstrated that the knockout of ENaC in the olfactory bulb of mice resulted in a decreased number of newly generated neurons and inhibited adult neurogenesis [112].”
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“There are mainly 3 subunits (α, β, and γ) to make up ENaC which transports Na+ from apical to basolateral side of alveolar epithelial cells and regulates the transport of water [10, 11].”
BackgroundMetabolic and proteostatic differences in quiescent and active neural stem cells
Yu, J., Chen, G., Zhu, H., Zhong, Y., Yang, Z., Jian, Z., & Xiong, X. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.375306 · Cited by 12 · see citing works
“Sodium influx induces membrane depolarization, which stimulates calcium exchangers and channels, leading to increased cytoplasmic calcium and NSC proliferation (Petrik et al., 2018).”
The year in review: progress in brain barriers and brain fluid research in 2018
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Design of neural organoids engineered by mechanical forces
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“Moreover, neural stem cells at brain ventricles sense the flow of CSF through their epithelium sodium channels (ENaC), thereby regulating their proliferation (Petrik et al., 2018).”
BackgroundInfluentialMotile cilia modulate neuronal and astroglial activity in the zebrafish larval brain
D’Gama, P. P., Jeong, I., Nygård, A. M., Jamali, A., Yaksi, E., & Jurisch‐Yaksi, N. (2025) · Cell Reports · doi:10.1016/j.celrep.2024.115195 · Cited by 10 · see citing works
Glial Populations in the Human Brain Following Ischemic Injury
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“Recent studies indicate that the choroid plexus regulates the proliferation of NSCs in the VZ-SVZ of the adult brain [39,40].”
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The neuronal transcription factor MEIS2 is a calpain-2 protease target
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“29 The deficiency of astrocytic Piezo1 in the hippocampus leads to a decrease in neurogenesis via an ATP-dependent downstream pathway, resulting in cognitive impairment.”
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MatriGrid® Based Biological Morphologies: Tools for 3D Cell Culturing
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“The fluid flow also has a direct influence on cell proliferation [61] by virtue of mechanical influences such as shear stress, pressure, and compression, which are essential factors for organ development and function [47].”
BackgroundAn analogue of the Prolactin Releasing Peptide reduces obesity and promotes adult neurogenesis
Jörgensen, S. K. M., Karnošová, A., Mazzaferro, S., Rowley, O., Chen, H. C., Robbins, S. J., Christofides, S. R., Merkle, F. T., Maletı́nská, L., & Petřík, D. (2023) · EMBO Reports · doi:10.1038/s44319-023-00016-2 · Cited by 7 · see citing works
“In drinking water, BrdU (1 mg/ml) was dissolved in sterile tap water with 1% sucrose (Petrik et al, 2018).”
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“Notably, ENaC functional deficiency not only affects the proliferative capacity of neural stem cells and neuroblasts but also leads to a significant reduction in newborn neurons (Petrik et al., 2018).”
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Self-citationSECS, drugs, and Rac1&Rho: regulation of EnNaC in vascular endothelial cells
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Recent Advancements in Engineering Strategies for Manipulating Neural Stem Cell Behavior
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Fibrinolytic niche is requested for alveolar type 2 cell-mediated alveologenesis and injury repairPreprint
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Comprehensive mapping of Epithelial Na+ channel α expression in the mouse brain
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Spinal scoliosis: insights into developmental mechanisms and animal models
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Upregulation of α-ENaC induces pancreatic β-cell dysfunction, ER stress, and SIRT2 degradation
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Mechanical regulation of nerve stem cells' multiple behaviors via GHz acoustic streaming
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Können osteopathische Behandlungen Einfluss auf die Neurogenese nehmen?
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Salt Taste, Nutrition, and Health
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Nutrition influences nervous system development by regulating neural stem cell homeostasis
Das, P., Akanksha, V., & Arya, R. (2022) · Proceedings of the Indian National Science Academy · doi:10.1007/s43538-022-00107-z · Cited by 1 · see citing works
“Sodium and Potassium channels on the NSCs and progenitor cells help the inward and outward flow of fluid and influence NSC homeostasis through various signalings (Bai et al., 2013; Petrik et al., 2018; Prüss et al., 2011; Wang et al., 2011).”
BackgroundEinklemmungsphänomene als Ursache für eine Parese des N. abducens
Engemann, K. (2023) · DO - Deutsche Zeitschrift für Osteopathie · doi:10.1055/a-1947-1642
Evaluating chemical effects on human neural cells through calcium imaging and deep learning
Ku, R. Y., Bansal, A., Dutta, D. J., Yamashita, S., Peloquin, J., Vu, D. N., Shen, Y., Uchida, T., Torii, M., & Hashimoto‐Torii, K. (2024) · iScience · doi:10.1016/j.isci.2024.111298
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Kumaria, A., Ashkan, K., & Macarthur, D. (2025) · Brain Tumor Pathology · doi:10.1007/s10014-025-00512-4
Ca 2+ -mediated protein citrullination regulates proliferation in the regenerating and malignant CNSPreprint
Crossman, S. H., Walpola, T., Douek, A. M., Wang, J., Khabooshan, M. A., Fung, C., Lieschke, G. J., Azimi, I., & Kaslin, J. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.25.701650
“…and prior evidence that CSF contact influences proliferative behaviour in neurogenic niches across the vertebrate lineage and in cancers of the CNS 16-19 , we first asked whether CSF circulation is altered during regeneration and whether such changes could contribute toward ERG reactivation after…”
Rodrigues, K. S., Yamashita, R., & Katada, S. (2026) · Frontiers in Neural Circuits · doi:10.3389/fncir.2026.1818927
“In parallel, ventricular-contacting NSCs can directly sense flow via epithelial sodium channels (ENaC), where Na influx triggers Ca 2 + signaling and ERK activation to promote NSC proliferation (Petrik et al., 2018).”
- Authors
- Petrik, D., Myoga, M. H., Grade, S., Gerkau, N. J., Pusch, M., Rose, C. R., Grothe, B., & Götz, M.
- Affiliations
- Max Planck Institute of Neurobiology (DE)
- Helmholtz Munich (DE)
- Heinrich Heine University Düsseldorf (DE)
- Munich Cluster for Systems Neurology (DE)
- Corresponding author
- Götz, Magdalena
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2018-06
- Volume
- 22
- Issue
- 6
- Pages
- 865-878.e8
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W2803588403
- Cited by
- 104
- References
- 93
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 12 · 2023: 7 · 2022: 8 · 2021: 16 · 2020: 25 · 2019: 15 · 2018: 4
- FWCI
- 5.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Site cant be reached (submittedVersion, other-oa)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- DFG
- Marie Curie Fellowship (PIIF-GA-2013-628603)
- DFG collaborative research center (SFB 870: Assembly and Function of Neuronal Circuits, CRC870/TP-A06, CRC870/TPB06)
- German Excellence Initiative (Graduate School of Systemic Neurosciences, LMU, GSN 82, and EXC1010 Synergy)
- priority program 1757 (Go13/1-2, Ro2327/8-2)
- priority program 1738
- advanced ERC grant (ChroNeuroRepair)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- epithelial sodium channel, adult neurogenesis, neural stem cells, subventricular zone, olfactory bulb, cell proliferation, cerebrospinal fluid flow, calcium signaling, calcium release-activated channels, ERK1/2 phosphorylation, ventricular fluid
- MeSH terms
- Animals, Cells, Cultured, Mice, Inbred C57BL, Mice, Knockout, Extracellular Fluid, Cell Proliferation, Mice, Epithelial Sodium Channels, Neural Stem Cells
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