Biology subjects

Shipley, F. B.

Publications and source records attributed to Shipley, F. B..

4 recordsLinked to original sources

bioRxiv2024

A choroid plexus apocrine secretion mechanism shapes CSF proteome and embryonic brain development

We discovered that apocrine secretion by embryonic choroid plexus (ChP) epithelial cells contributes to the cerebrospinal fluid (CSF) proteome and influences brain development in mice. The apocrine response relies on sustained intracellular calcium signaling and calpain-mediated cytoskeletal remodeling. It rapidly alters the embryonic CSF proteome, activating neural progenitors lining the brains ventricles. Supraphysiological apocrine secretion induced during mouse development by maternal administration of a serotonergic 5HT2C receptor agonist dysregulates offspring cerebral cortical development, alters the fate of CSF-contacting neural progenitors, and ultimately changes adult social behaviors. Critically, exposure to maternal illness or to the psychedelic drug LSD during pregnancy also overactivates the ChP, inducing excessive secretion. Collectively, our findings demonstrate a new mechanism by which maternal exposure to diverse stressors disrupts in utero brain development.

neuroscience↗

bioRxiv2023

A collaboration between immune cells and the choroid plexus epithelium in brain inflammation

The choroid plexus (ChP) is a vital brain barrier and source of cerebrospinal fluid (CSF). Here, we use chronic two-photon imaging in awake mice and single-cell transcriptomics to demonstrate that in addition to these roles, the ChP is a complex immune organ that regulates brain inflammation. In a mouse meningitis model, neutrophils and monocytes accumulated in ChP stroma and surged across the epithelial barrier into the CSF. Bi-directional recruitment of monocytes from the periphery and, unexpectedly, macrophages from the CSF to the ChP helped eliminate neutrophils and repair the barrier. Transcriptomic analyses detailed the molecular steps accompanying this process, including the discovery of epithelial cells that transiently specialized to nurture immune cells, coordinate their recruitment, survival, and differentiation, and ultimately, control the opening/closing of the ChP brain barrier. Collectively, we provide a new conceptual understanding and comprehensive roadmap of neuroinflammation at the ChP brain barrier.

neuroscience↗

bioRxiv2020

Non-canonical, potassium-driven cerebrospinal fluid clearance

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.

neuroscience↗

bioRxiv2019

A cellular and spatial map of the choroid plexus across brain ventricles and ages

The choroid plexus (ChP), located in each brain ventricle, produces cerebrospinal fluid (CSF) and forms the blood-CSF barrier, but is under-characterized. Here, we combine single cell RNA-Seq and spatial mapping of RNA and proteins to construct an atlas of each ChP in the developing and adult mouse brain. Each ChP comprises of epithelial, endothelial, mesenchymal, immune, neuronal, and glial cells, with distinct subtypes, differentiation states and anatomical locations. Epithelial, fibroblast, and macrophage populations had ventricle-specific, regionalized gene expression programs across the developing brain. Key cell types are retained in adult, with loss of developmental signatures and maturation of ventricle-specific regionalization in the epithelial cells. Expression of cognate ligand-receptor pairs across cell subtypes suggests substantial cell-cell interactions within the ChP. Our atlas sheds new light on the development and function of the ChP brain barrier system, and will facilitate future studies on its role in brain development, homeostasis and disease.

neuroscience↗