Multiple Na,K-ATPase Subunits Colocalize in the Brush Border of Mouse Choroid Plexus Epithelial Cells

Christensen, Inga Baasch; Liu, Cheng; Brewer, Jonathan R.; Bartsch, Udo; Fenton, Robert A.; Damkier, Helle Hasager; Prætorius, Jeppe

doi:10.3390/ijms22041569

Cited by 3 publications

(2 citation statements)

References 33 publications

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“…The NKCC1, NBCe2, NHE1, and Na + /K + -ATPase (α1) localize to the luminal choroidal membrane in all tested species [50][51][52][53][54] , here verified for NKCC1 in the rat choroid plexus (Supplementary Fig. 4b).…”

Section: Choroidal Transport Proteins In the Luminal Membranesupporting

confidence: 67%

Cerebrospinal fluid formation is controlled by membrane transporters to modulate intracranial pressure

Oernbo

Steffensen

Khamesi

et al. 2021

Preprint

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Disturbances in the brain fluid balance can lead to life-threatening elevation in the intracranial pressure (ICP), which represents a vast clinical challenge. Nevertheless, the molecular mechanisms governing cerebrospinal fluid (CSF) secretion are largely unresolved, thus preventing targeted and efficient pharmaceutical therapy of cerebral pathologies involving elevated ICP. Here, we employed experimental rats to demonstrate low osmotic water permeability of the choroid plexus, lack of an osmotic gradient across this tissue, and robust CSF secretion against osmotic gradients. Together, these results illustrate that CSF secretion occurs independently of conventional osmosis, which challenges the existing assumption that CSF production is driven entirely by bulk osmotic forces across the CSF-secreting choroid plexus. Instead, we reveal that the choroidal Na+/K+/Cl− cotransporter NKCC1, Na+/HCO3− cotransporter NBCe2, and Na+/K+-ATPase are actively involved in CSF production and propose a molecular mode of water transport supporting CSF production in this secretory tissue. Further, we demonstrate that inhibition of NKCC1 directly reduces the ICP, illustrating that altered CSF secretion may be employed as a strategy to modulate ICP. These insights identify new promising therapeutic targets against brain pathologies associated with elevated ICP.

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Section: Choroidal Transport Proteins In the Luminal Membranesupporting

confidence: 67%

Cerebrospinal fluid formation is controlled by membrane transporters to modulate intracranial pressure

Oernbo

Steffensen

Khamesi

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…The NKCC1, NBCe2, NHE1, and Na + /K + -ATPase (α1) localize to the luminal choroidal membrane in all tested species [52][53][54][55][56], here verified for NKCC1 in the rat choroid plexus (Additional file 1: Fig. S4b).…”

Section: Choroidal Transport Proteins In the Luminal Membranesupporting

confidence: 63%

Membrane transporters control cerebrospinal fluid formation independently of conventional osmosis to modulate intracranial pressure

Oernbo

Steffensen

Khamesi

et al. 2022

Fluids Barriers CNS

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Background Disturbances in the brain fluid balance can lead to life-threatening elevation in the intracranial pressure (ICP), which represents a vast clinical challenge. Nevertheless, the details underlying the molecular mechanisms governing cerebrospinal fluid (CSF) secretion are largely unresolved, thus preventing targeted and efficient pharmaceutical therapy of cerebral pathologies involving elevated ICP. Methods Experimental rats were employed for in vivo determinations of CSF secretion rates, ICP, blood pressure and ex vivo excised choroid plexus for morphological analysis and quantification of expression and activity of various transport proteins. CSF and blood extractions from rats, pigs, and humans were employed for osmolality determinations and a mathematical model employed to determine a contribution from potential local gradients at the surface of choroid plexus. Results We demonstrate that CSF secretion can occur independently of conventional osmosis and that local osmotic gradients do not suffice to support CSF secretion. Instead, the CSF secretion across the luminal membrane of choroid plexus relies approximately equally on the Na+/K+/2Cl− cotransporter NKCC1, the Na+/HCO3− cotransporter NBCe2, and the Na+/K+-ATPase, but not on the Na+/H+ exchanger NHE1. We demonstrate that pharmacological modulation of CSF secretion directly affects the ICP. Conclusions CSF secretion appears to not rely on conventional osmosis, but rather occur by a concerted effort of different choroidal transporters, possibly via a molecular mode of water transport inherent in the proteins themselves. Therapeutic modulation of the rate of CSF secretion may be employed as a strategy to modulate ICP. These insights identify new promising therapeutic targets against brain pathologies associated with elevated ICP.

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The Lego hypothesis of tissue morphogenesis: stereotypic organization of parallel orientational cell adhesions for epithelial self‐assembly

Zhang,

Wei

2024

Biological Reviews

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How tissues develop distinct structures remains poorly understood. We propose herein the Lego hypothesis of tissue morphogenesis, which states that during tissue morphogenesis, the topographical properties of cell surface adhesion molecules can be dynamically altered and polarised by regulating the spatiotemporal expression and localization of orientational cell adhesion (OCA) molecules cell‐autonomously and non‐cell‐autonomously, thus modulating cells into unique Lego pieces for self‐assembling into distinct cytoarchitectures. This concept can be exemplified by epithelial morphogenesis, in which cells are coalesced into a sheet by many types of adhesions. Among them, parallel OCAs (pOCAs) at the lateral cell membranes are essential for configuring cells in parallel. Major pOCAs include Na+/K+‐ATPase‐mediated adhesions, Crumbs‐mediated adhesions, tight junctions, adherens junctions, and desmosomes. These pOCAs align in stereotypical orders along the apical‐to‐basal axis, and their absolute positioning is also regulated. Such spatial organization of pOCAs underlies proper epithelial morphogenesis. Thus, a key open question about tissue morphogenesis is how to regulate OCAs to make compatible adhesive cellular Lego pieces for tissue construction.

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Multiple Na,K-ATPase Subunits Colocalize in the Brush Border of Mouse Choroid Plexus Epithelial Cells

Cited by 3 publications

References 33 publications

Cerebrospinal fluid formation is controlled by membrane transporters to modulate intracranial pressure

Cerebrospinal fluid formation is controlled by membrane transporters to modulate intracranial pressure

Membrane transporters control cerebrospinal fluid formation independently of conventional osmosis to modulate intracranial pressure

The Lego hypothesis of tissue morphogenesis: stereotypic organization of parallel orientational cell adhesions for epithelial self‐assembly

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