TY - JOUR
T1 - Choroid plexus apocrine secretion shapes CSF proteome during mouse brain development
AU - Courtney, Ya’el
AU - Head, Joshua P.
AU - Dani, Neil
AU - Chechneva, Olga V.
AU - Shipley, Frederick B.
AU - Zhang, Yong
AU - Holtzman, Michael J.
AU - Sadegh, Cameron
AU - Libermann, Towia A.
AU - Lehtinen, Maria K.
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/7
Y1 - 2025/7
N2 - 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-HT2C 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.
AB - 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-HT2C 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.
UR - http://www.scopus.com/inward/record.url?scp=105006886192&partnerID=8YFLogxK
U2 - 10.1038/s41593-025-01972-9
DO - 10.1038/s41593-025-01972-9
M3 - Article
C2 - 40437054
AN - SCOPUS:105006886192
SN - 1097-6256
VL - 28
SP - 1446
EP - 1459
JO - Nature neuroscience
JF - Nature neuroscience
IS - 7
ER -