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

Xu, Huixin; Fame, Ryann M.; Sadegh, Cameron; Sutin, Jason; Naranjo, Christopher A; Syau, Della; Cui, Jin; Shipley, Frederick B.; Vernon, Amanda; Gao, Fan; Zhang, Yong; Holtzman, Michael J.; Heiman, Myriam; Warf, Benjamin C.; Lin, Pei-Yi; Lehtinen, Maria K.

doi:10.1038/s41467-020-20666-3

Cited by 77 publications

(82 citation statements)

References 87 publications

(115 reference statements)

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“…We adopted an adeno-associated viral (AAV) approach using a serotype with tropism for ChP epithelial cells (Cui et al, 2020;Haddad et al, 2013;Xu et al, 2021) to test whether supplemental Meis1 expression would be sufficient to influence 4V ChP morphology (Fig. S7A,B).…”

Section: Meis1 Regulates Expression Of Wnt5a In 4v Chp Epitheliummentioning

confidence: 99%

MEIS-WNT5A axis regulates development of fourth ventricle choroid plexus

et al. 2021

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The choroid plexus (ChP) produces cerebrospinal fluid and forms an essential brain barrier. ChP tissues form in each brain ventricle, each one adopting a distinct shape, but remarkably little is known about the mechanisms underlying ChP development. Here, we show that epithelial WNT5A is crucial for determining fourth ventricle (4V) ChP morphogenesis and size in mouse. Systemic Wnt5a knockout, or forced Wnt5a overexpression beginning at embryonic day 10.5, profoundly reduced ChP size and development. However, Wnt5a expression was enriched in Foxj1-positive epithelial cells of 4V ChP plexus, and its conditional deletion in these cells affected the branched, villous morphology of the 4V ChP. We found that WNT5A was enriched in epithelial cells localized to the distal tips of 4V ChP villi, where WNT5A acted locally to activate non-canonical WNT signaling via ROR1 and ROR2 receptors. During 4V ChP development, MEIS1 bound to the proximal Wnt5a promoter, and gain- and loss-of-function approaches demonstrated that MEIS1 regulated Wnt5a expression. Collectively, our findings demonstrate a dual function of WNT5A in ChP development and identify MEIS transcription factors as upstream regulators of Wnt5a in the 4V ChP epithelium.

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Section: Meis1 Regulates Expression Of Wnt5a In 4v Chp Epitheliummentioning

confidence: 99%

MEIS-WNT5A axis regulates development of fourth ventricle choroid plexus

et al. 2021

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“…However, the NKCC1 transport direction may be reversed under certain circumstances such as during early development or in dissociated choroid plexus epithelial cells 81,94,95 .…”

Section: Discussionmentioning

confidence: 99%

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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“…Conceivable options are a clearing via meningeal lymphatic vessels or via the choroid plexus. [69][70][71][72] After SAH, the absorptive function of these structures might be impaired. On the one hand, CSF-Hb may play an etiological role as a toxin in this functional impairment; on the other hand, its CSF concentration may be influenced by a reduced clearance via these structures.…”

Section: Limitations and Pertinent Research Questionsmentioning

confidence: 99%

Cerebrospinal fluid hemoglobin drives subarachnoid hemorrhage-related secondary brain injury

Akeret

Buzzi

Schaer

et al. 2021

J Cereb Blood Flow Metab

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Secondary brain injury after aneurysmal subarachnoid hemorrhage (SAH-SBI) contributes to poor outcomes in patients after rupture of an intracranial aneurysm. The lack of diagnostic biomarkers and novel drug targets represent an unmet need. The aim of this study was to investigate the clinical and pathophysiological association between cerebrospinal fluid hemoglobin (CSF-Hb) and SAH-SBI. In a cohort of 47 patients, we collected daily CSF-samples within 14 days after aneurysm rupture. There was very strong evidence for a positive association between spectrophotometrically determined CSF-Hb and SAH-SBI. The accuracy of CSF-Hb to monitor for SAH-SBI markedly exceeded that of established methods (AUC: 0.89 [0.85-0.92]). Temporal proteome analysis revealed erythrolysis accompanied by an adaptive macrophage response as the two dominant biological processes in the CSF-space after aneurysm rupture. Ex-vivo experiments on the vasoconstrictive and oxidative potential of Hb revealed critical inflection points overlapping CSF-Hb thresholds in patients with SAH-SBI. Selective depletion and in-solution neutralization by haptoglobin or hemopexin efficiently attenuated the vasoconstrictive and lipid peroxidation activities of CSF-Hb. Collectively, the clinical association between high CSF-Hb levels and SAH-SBI, the underlying pathophysiological rationale, and the favorable effects of haptoglobin and hemopexin in ex-vivo experiments position CSF-Hb as a highly attractive biomarker and potential drug target.

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

Cited by 77 publications

References 87 publications

MEIS-WNT5A axis regulates development of fourth ventricle choroid plexus

MEIS-WNT5A axis regulates development of fourth ventricle choroid plexus

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

Cerebrospinal fluid hemoglobin drives subarachnoid hemorrhage-related secondary brain injury

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