Choroid plexus apocrine secretion shapes CSF proteome during mouse brain development

Ya'el Courtney; Joshua P Head; Neil Dani; Olga V Chechneva; Frederick B Shipley; Yong Zhang; Michael J Holtzman; Cameron Sadegh; Towia A Libermann; Maria K Lehtinen

doi:10.1038/s41593-025-01972-9

Choroid plexus apocrine secretion shapes CSF proteome during mouse brain development

Nat Neurosci. 2025 Jul;28(7):1446-1459. doi: 10.1038/s41593-025-01972-9. Epub 2025 May 28.

Authors

Ya'el Courtney^{1

2}, Joshua P Head¹, Neil Dani^{1

3}, Olga V Chechneva⁴, Frederick B Shipley^{1

5}, Yong Zhang⁶, Michael J Holtzman⁶, Cameron Sadegh⁴, Towia A Libermann⁷, Maria K Lehtinen^{8

9

10}

Affiliations

¹ Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
² Graduate Program in Neuroscience, Harvard Medical School, Boston, MA, USA.
³ Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
⁴ Department of Neurosurgery, University of California, Davis, Sacramento, CA, USA.
⁵ Graduate Program in Biophysics, Harvard University, Cambridge, MA, USA.
⁶ Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
⁷ Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
⁸ Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. maria.lehtinen@childrens.harvard.edu.
⁹ Graduate Program in Neuroscience, Harvard Medical School, Boston, MA, USA. maria.lehtinen@childrens.harvard.edu.
¹⁰ Graduate Program in Biophysics, Harvard University, Cambridge, MA, USA. maria.lehtinen@childrens.harvard.edu.

Abstract

The choroid plexus (ChP) regulates cerebrospinal fluid (CSF) composition, providing essential molecular cues for brain development; yet, embryonic ChP secretory mechanisms remain poorly defined. Here we identify apocrine secretion by embryonic ChP epithelial cells as a key regulator of the CSF proteome and neurodevelopment in male and female mice. We demonstrate that the activation of serotonergic 5-HT_2C receptors (by WAY-161503) triggers sustained Ca²⁺ signaling, driving high-volume apocrine secretion in mouse and human ChP. This secretion alters the CSF proteome, stimulating neural progenitors lining the brain's ventricles and shifting their developmental trajectory. Inducing ChP secretion in utero in mice disrupts neural progenitor dynamics, cerebral cortical architecture and offspring behavior. Additionally, illness or lysergic acid diethylamide exposure during pregnancy provokes coordinated ChP secretion in the mouse embryo. Our findings reveal a fundamental secretory pathway in the ChP that shapes brain development, highlighting how its disruption can have lasting consequences for brain health.

MeSH terms

Animals
Brain* / embryology
Brain* / growth & development
Brain* / metabolism
Cerebrospinal Fluid* / metabolism
Choroid Plexus* / embryology
Choroid Plexus* / metabolism
Female
Humans
Male
Mice
Mice, Inbred C57BL
Pregnancy
Proteome* / metabolism

Substances

Proteome

Abstract

MeSH terms

Substances

Grants and funding