Elusive role of the Na-K-2Cl cotransporter in the choroid plexus

Delpire, Eric; Gagnon, Kenneth B.

doi:10.1152/ajpcell.00490.2018

Cited by 19 publications

(18 citation statements)

References 20 publications

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“…2g ), and therefore overexpression without increased activation via phosphorylation was unlikely to influence total NKCC1 transport in adulthood. While the exact transport direction of NKCC1 in adult ChP is still under debate 24 , the consistency in ventricular volume from P14 into later life supports our working model that because a relatively small proportion of ChP NKCC1 was phosphorylated in mice P14 and older (Fig. 2g ), NKCC1 levels are not rate-limiting and thus OE would not as substantially impact ChP functions in older animals.…”

Section: Resultssupporting

confidence: 68%

Choroid plexus NKCC1 mediates cerebrospinal fluid clearance during mouse early postnatal development

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Sadegh

et al. 2021

Nat Commun

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Cerebrospinal fluid (CSF) provides vital support for the brain. Abnormal CSF accumulation, such as hydrocephalus, can negatively affect perinatal neurodevelopment. The mechanisms regulating CSF clearance during the postnatal critical period are unclear. Here, we show that CSF K+, accompanied by water, is cleared through the choroid plexus (ChP) during mouse early postnatal development. We report that, at this developmental stage, the ChP showed increased ATP production and increased expression of ATP-dependent K+ transporters, particularly the Na+, K+, Cl−, and water cotransporter NKCC1. Overexpression of NKCC1 in the ChP resulted in increased CSF K+ clearance, increased cerebral compliance, and reduced circulating CSF in the brain without changes in intracranial pressure in mice. Moreover, ChP-specific NKCC1 overexpression in an obstructive hydrocephalus mouse model resulted in reduced ventriculomegaly. Collectively, our results implicate NKCC1 in regulating CSF K+ clearance through the ChP in the critical period during postnatal neurodevelopment in mice.

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Section: Resultssupporting

confidence: 68%

Choroid plexus NKCC1 mediates cerebrospinal fluid clearance during mouse early postnatal development

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Sadegh

et al. 2021

Nat Commun

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“…The difference in ventricle sizes from these same mice was sustained up to our final measurement at P50 (AAV-GFP: 3.12 ± 0.59 mm 3 vs. AAV-NKCC1: 1.28 ± 0.28 mm 3 , * p = 0.0182). While the exact transport direction of NKCC1 in adult ChP is still under debate (Delpire and Gagnon, 2019), the consistency in ventricular volume from P14 into later life supports our working model that because a relatively small proportion of ChP NKCC1 was phosphorylated in mice P14 and older ( Fig. 2G), NKCC1 levels are not rate-limiting and thus OE would not as substantially impact ChP functions in older animals.…”

Section: Chp Nkcc1 Actively Mediates Csf Clearance During the Early Psupporting

confidence: 67%

“…NKCC1 is a bidirectional transporter, recently discovered to be an important cotransporter of water in the adult ChP (Steffensen et al, 2018). Although clearly established as a key molecular mechanism of CSF regulation, ChP NKCC1 transport direction and its determinants in vivo have been actively debated due to the technical challenges of 1) specifically manipulating ChP NKCC1 without affecting NKCC1 in other CSF-contacting cells, instead of ICV application of chemicals such as NKCC1 inhibitor bumetanide; and 2) accurately determining intracellular ion levels of ChP epithelial cells, and therefore ion gradients, under physiological conditions, as summarized in Supplementary Table 1 and reviewed by Delpire and Gagnon (Delpire and Gagnon, 2019). Our in vivo "gain-of-function" approach effectively bypasses the abovementioned technical limitations.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, historical clinical observations suggest some absorptive functions of the ChP (Milhorat et al, 1970) which is supported by animal studies (Oreskovic et al, 2017). Finally, broad transcriptional changes of the machinery regulating fluid/ion transport support the concept of temporally dynamic and possibly contextdependent ChP functions in determining net directionality of CSF transport (Liddelow et al, 2013, Delpire andGagnon, 2019).…”

Section: Introductionmentioning

confidence: 86%

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Non-canonical, potassium-driven cerebrospinal fluid clearance

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Sadegh

et al. 2020

Preprint

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Cerebrospinal fluid (CSF) provides vital support for the brain. Abnormal CSF accumulation is deleterious for perinatal neurodevelopment, but how CSF leaves the brain during this critical period is unknown. We found in mice a postnatal neurodevelopmental transition phase featuring precipitous CSF K+ clearance, accompanied by water, through the choroid plexus (ChP). The period corresponds to a human fetal stage when canonical CSF clearance pathways have yet to form and congenital hydrocephalus begins to manifest. Unbiased ChP metabolic and ribosomal profiling highlighted this transition phase with increased ATP yield and activated energy-dependent K+ transporters, in particular the Na+-K+-Cl- and water cotransporter NKCC1. ChP-targeted NKCC1 overexpression enhanced K+-driven CSF clearance and enabled more permissive cerebral hydrodynamics. Moreover, ventriculomegaly in an obstructive hydrocephalus model was improved by ChP-targeted NKCC1 overexpression. Collectively, we identified K+-driven CSF clearance through ChP during a transient but critical neurodevelopmental phase, with translational value for pathologic conditions.

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“…It has been proposed that it acts as an efflux transporter at the choroid plexus and is involved in CSF secretion but this has been questioned by Gregoriades et al [74] who have provided evidence for influx activity. This is a difficult issue to resolve because different experimental preparations may alter cellular ion concentrations [75]. This is an important issue as NKCC1 is one potential target for altering CSF secretion and brain intracranial pressure [76].…”

Section: Choroid Plexusmentioning

confidence: 99%

This was the year that was: brain barriers and brain fluid research in 2019

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Jones²,

Drewes

2020

Fluids Barriers CNS

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This editorial highlights advances in brain barrier and brain fluid research published in 2019, as well as addressing current controversies and pressing needs. Topics include recent advances related to: the cerebral endothelium and the neurovascular unit; the choroid plexus, arachnoid membrane; cerebrospinal fluid and the glymphatic hypothesis; the impact of disease states on brain barriers and brain fluids; drug delivery to the brain; and translation of preclinical data to the clinic. This editorial also mourns the loss of two important figures in the field, Malcolm B. Segal and Edward G. Stopa.

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Elusive role of the Na-K-2Cl cotransporter in the choroid plexus

Cited by 19 publications

References 20 publications

Choroid plexus NKCC1 mediates cerebrospinal fluid clearance during mouse early postnatal development

Choroid plexus NKCC1 mediates cerebrospinal fluid clearance during mouse early postnatal development

Non-canonical, potassium-driven cerebrospinal fluid clearance

This was the year that was: brain barriers and brain fluid research in 2019

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