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

Xu, Huixin and Fame, Ryann M. and Sadegh, Cameron and Sutin, Jason and Naranjo, Christopher and Syau, Della and Cui, Jin and Shipley, Frederick B. and Vernon, Amanda and Gao, Fan and Zhang, Yong and Holtzman, Michael J. and Heiman, Myriam and Warf, Benjamin C. and Lin, Pei-Yi and Lehtinen, Maria K. (2021) Choroid plexus NKCC1 mediates cerebrospinal fluid clearance during mouse early postnatal development. Nature Communications, 12 . Art. No. 447. ISSN 2041-1723. PMCID PMC7815709. doi:10.1038/s41467-020-20666-3.

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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.

Item Type:Article
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URLURL TypeDescription CentralArticle
Xu, Huixin0000-0003-4190-4244
Fame, Ryann M.0000-0002-8244-2624
Sadegh, Cameron0000-0003-2231-9015
Sutin, Jason0000-0002-9492-3978
Vernon, Amanda0000-0003-4336-2135
Holtzman, Michael J.0000-0001-8750-3716
Lin, Pei-Yi0000-0003-3685-3331
Lehtinen, Maria K.0000-0002-7243-2967
Additional Information:© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit Received 23 June 2020. Accepted 10 December 2020. Published 19 January 2021. We thank members of the Lehtinen, Heiman, and Warf labs for helpful discussions; Nancy Chamberlin for advice on the manuscript; Katia Georgopoulos for sharing the Chd4 fl/fl mouse line and associated genotyping methods; P. Ellen Grant for the ICP monitor. We thank the following facilities and personnel: Maria Ericsson and HMS EM facility; Yaotang Wu and Michael Marcotrigiano and BCH Small Animal Imaging Laboratory; the MIT BioMicro Center (TRAP sequencing); BCH viral core and University of Pennsylvania Vector Core; the IDDRC Cellular Imaging Core and Harvard Digestive Diseases Center Imaging Core. NIH T32 HL110852 (R.M.F. and J.C.); William Randolph Hearst Fund (J.C.); NSF Graduate Research Fellowship Program (F.B.S.); OFD/BTREC/CTREC Faculty Development Fellowship Award (R.M.F.); Simons Foundation Autism Research Awards (IDs 590293 and 645596 for C.N. and D.S., respectively). NIH R01 AI130591 and R35 HL145242 (M.J.H.); NIH R00 HD083512 (P.-Y.L.); and R01 HD096693 (P.-Y.L. and B.C.W.); BCH Pilot Grant, Pediatric Hydrocephalus Foundation, Hydrocephalus Association, Human Frontier Science Program (HFSP) research program grant #RGP0063/2018, NIH R01 NS088566, the New York Stem Cell Foundation (M.K.L.); BCH IDDRC 1U54HD090255 and BCH viral core P30EY012196. M.K.L. is a New York Stem Cell Foundation—Robertson Investigator. Data availability. Sequencing data from TRAP study (for Fig. 2 and Supplementary Fig. 4) are available in GEO (; accession number 138970). All other data are available from the authors. All biological material were either directly commercially available or are available upon request from the lab. Source data are provided with this paper. Code availability. The custom MatLab code is provided as supplementary for Fig. 1 and Supplementary Fig. 3 (Fig1_Supporting_MitoDistance.m). The code is also available on GitHub ( All other data are available in the main text or the supplementary materials. Author Contributions. H.X., R.M.F., C.S., J.S., P.-Y.L., B.C.W., F.B.S., J.C., D.S., C.N., and M.K.L. designed and performed experiments; H.X., R.M.F., C.S., and J.S. analyzed the data; Y.Z. and M.J.H. provided material; A.V., F.G., and M.H. provided technological support; H.X., R.M.F., and M.K.L. wrote the manuscript. All co-authors edited the manuscript. The authors declare no competing interests. Peer review information. Nature Communications thanks Norman Saunders and the other anonymous reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.
Funding AgencyGrant Number
NIH Predoctoral FellowshipT32 HL110852
William Randolph Hearst FundUNSPECIFIED
NSF Graduate Research FellowshipUNSPECIFIED
Boston Children's HospitalUNSPECIFIED
Simons Foundation590293
Simons Foundation645596
NIHR01 AI130591
NIHR35 HL145242
NIHR00 HD083512
NIHR01 HD096693
Pediatric Hydrocephalus FoundationUNSPECIFIED
Hydrocephalus AssociationUNSPECIFIED
Human Frontier Science ProgramRGP0063/2018
NIHR01 NS088566
New York Stem Cell FoundationUNSPECIFIED
PubMed Central ID:PMC7815709
Record Number:CaltechAUTHORS:20210121-101410324
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Official Citation:Xu, H., Fame, R.M., Sadegh, C. et al. Choroid plexus NKCC1 mediates cerebrospinal fluid clearance during mouse early postnatal development. Nat Commun 12, 447 (2021).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:107624
Deposited By: George Porter
Deposited On:21 Jan 2021 22:05
Last Modified:16 Nov 2021 19:04

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