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. (2020) Non-canonical, potassium-driven cerebrospinal fluid clearance. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20200805-095526447
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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.
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| 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. | ||||||||||||||||||||||||||||||||||
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| Subject Keywords: | cerebrospinal fluid; clearance; potassium; choroid plexus; development; NKCC1; hydrocephalus | ||||||||||||||||||||||||||||||||||
| DOI: | 10.1101/2020.08.03.234260 | ||||||||||||||||||||||||||||||||||
| Record Number: | CaltechAUTHORS:20200805-095526447 | ||||||||||||||||||||||||||||||||||
| Persistent URL: | https://resolver.caltech.edu/CaltechAUTHORS:20200805-095526447 | ||||||||||||||||||||||||||||||||||
| Official Citation: | Non-canonical, potassium-driven cerebrospinal fluid clearance. Huixin Xu, Ryann M Fame, Cameron Sadegh, Jason Sutin, Christopher Naranjo, Della Syau, Jin Cui, Frederick B Shipley, Amanda Vernon, Fan Gao, Yong Zhang, Michael J Holtzman, Myriam Heiman, Benjamin C Warf, Pei-Yi Lin, Maria K Lehtinen. bioRxiv 2020.08.03.234260; doi: https://doi.org/10.1101/2020.08.03.234260 | ||||||||||||||||||||||||||||||||||
| Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | ||||||||||||||||||||||||||||||||||
| ID Code: | 104751 | ||||||||||||||||||||||||||||||||||
| Collection: | CaltechAUTHORS | ||||||||||||||||||||||||||||||||||
| Deposited By: | Tony Diaz | ||||||||||||||||||||||||||||||||||
| Deposited On: | 05 Aug 2020 18:58 | ||||||||||||||||||||||||||||||||||
| Last Modified: | 16 Nov 2021 18:34 |
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