CaltechAUTHORS
Published August 4, 2020 | Version Submitted + Supplemental Material
Discussion Paper Open

Non-canonical, potassium-driven cerebrospinal fluid clearance

Creators

  • 1. ROR icon Boston Children's Hospital
  • 2. ROR icon Massachusetts General Hospital
  • 3. ROR icon Harvard University
  • 4. ROR icon Broad Institute
  • 5. ROR icon Massachusetts Institute of Technology
  • 6. ROR icon Washington University in St. Louis

Abstract

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.

Additional Information

The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. Posted August 04, 2020. We thank members of the Lehtinen, Heiman, and Warf labs for helpful discussions; Nancy Chamberlin for critical reading of 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 facility 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. Funding: NIH T32 HL110852 (RMF and JC); William Randolph Hearst Fund (JC); NSF Graduate Research Fellowship Program (FBS); OFD/BTREC/CTREC Faculty Development Fellowship Award (RMF); Simons Foundation Autism Research Awards (IDs 590293 and 645596 for CN and DS, respectively). NIH R01 AI130591 and R35 HL145242 (MJH); NIH R00 HD083512 (P-YL) and R01 HD096693 (P-YL & BCW); 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 (MKL); and BCH IDDRC 1U54HD090255. M.K. Lehtinen is a New York Stem Cell Foundation – Robertson Investigator. 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 that no competing interests exist.

Attached Files

Submitted - 2020.08.03.234260v1.full.pdf

Supplemental Material - media-1.pdf

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Additional details

Identifiers

Eprint ID
104751
Resolver ID
CaltechAUTHORS:20200805-095526447

Funding

NIH Predoctoral Fellowship
T32 HL110852
William Randolph Hearst Foundation
NSF Graduate Research Fellowship
Boston Children's Hospital
Simons Foundation
590293
Simons Foundation
645596
NIH
R01 AI130591
NIH
R35 HL145242
NIH
R00 HD083512
NIH
R01 HD096693
Pediatric Hydrocephalus Foundation
Hydrocephalus Association
Human Frontier Science Program
RGP0063/2018
NIH
R01 NS088566
New York Stem Cell Foundation
NIH
1U54HD090255

Dates

Created
2020-08-05
Created from EPrint's datestamp field
Updated
2021-11-16
Created from EPrint's last_modified field