The choroid plexus (ChP) is the principal source of cerebrospinal fluid (CSF), which has accepted roles as a fluid cushion and a sink for nervous system waste in vertebrates. Various animal models ...have provided insights into how the ChP-CSF system develops and matures. In addition, recent studies have uncovered new, active roles for this dynamic system in the regulation of neural stem cells, critical periods and the overall health of the nervous system. Together, these findings have brought about a paradigm shift in our understanding of brain development and health, and have stimulated new initiatives for the treatment of neurological disease.
The choroid plexus (ChP), an epithelial bilayer containing a network of mesenchymal, immune, and neuronal cells, forms the blood–cerebrospinal fluid (CSF) barrier (BCSFB). While best recognized for ...secreting CSF, the ChP is also a hotbed of immune cell activity and can provide circulating peripheral immune cells with passage into the central nervous system (CNS). Here, we review recent studies on ChP immune cells, with a focus on the ontogeny, development, and behaviors of ChP macrophages, the principal resident immune cells of the ChP. We highlight the implications of immune cells for ChP barrier function, CSF cytokines and volume regulation, and their contribution to neurodevelopmental disorders, with possible age-specific features to be elucidated in the future.
The choroid plexus (ChP) provides a critical brain barrier that is also home to diverse and dynamic immune cell populations throughout life, as revealed by recent transcriptomic studies.ChP macrophages represent the largest class of ChP immune cells and show heterogeneity.Advances in in vivo imaging provide unobstructed views of ChP immune cells in their physiological setting in the brain’s ventricles.Environmental cues and tightly knit receptor–ligand networks at the ChP govern immune cell recruitment and infiltration from the periphery into the central nervous system (CNS).The relevance of immune cell trafficking and dynamics at the ChP is increasingly appreciated in the context of neurological conditions involving neuroinflammation.
Cortical development depends on the active integration of cell-autonomous and extrinsic cues, but the coordination of these processes is poorly understood. Here, we show that the apical complex ...protein Pals1 and Pten have opposing roles in localizing the Igf1R to the apical, ventricular domain of cerebral cortical progenitor cells. We found that the cerebrospinal fluid (CSF), which contacts this apical domain, has an age-dependent effect on proliferation, much of which is attributable to Igf2, but that CSF contains other signaling activities as well. CSF samples from patients with glioblastoma multiforme show elevated Igf2 and stimulate stem cell proliferation in an Igf2-dependent manner. Together, our findings demonstrate that the apical complex couples intrinsic and extrinsic signaling, enabling progenitors to sense and respond appropriately to diffusible CSF-borne signals distributed widely throughout the brain. The temporal control of CSF composition may have critical relevance to normal development and neuropathological conditions.
► Embryonic CSF distributes many factors to the developing brain ► CSF Igf2 binds to progenitors and stimulates their proliferation ► Pals1 and Pten regulate Igf1 receptor expression ► Igf2 in glioblastoma CSF regulates progenitor proliferation and disease state
We summarize recent work illuminating how cerebrospinal fluid (CSF) regulates brain function. More than a protective fluid cushion and sink for waste, the CSF is an integral CNS component with ...dynamic and diverse roles emerging in parallel with the developing CNS. This review examines the current understanding about early CSF and its maturation and roles during CNS development and discusses open questions in the field. We focus on developmental changes in the ventricular system and CSF sources (including neural progenitors and choroid plexus). We also discuss concepts related to the development of fluid dynamics including flow, perivascular transport, drainage, and barriers.
Fame and Lehtinen summarize recent work illuminating how cerebrospinal fluid (CSF) regulates brain function. They discuss early CSF, its maturation and roles during CNS development, and open questions in the field as well as concepts related to the development of fluid dynamics, including flow, perivascular transport, drainage, and barriers.
Located in each brain ventricle, choroid plexus (ChP) tissue forms a blood-CSF barrier and produces cerebrospinal fluid (CSF) and other supportive factors. Sheets of ChP epithelial cells enclose a ...vascularized stroma of mesenchymal, immune, and neuron/glia-like cells. Burgeoning ChP studies are revealing its complex set of functions across the lifespan. To view this SnapShot, open or download the PDF.
Located in each brain ventricle, choroid plexus (ChP) tissue forms a blood-CSF barrier and produces cerebrospinal fluid (CSF) and other supportive factors. Sheets of ChP epithelial cells enclose a vascularized stroma of mesenchymal, immune, and neuron/glia-like cells. Burgeoning ChP studies are revealing its complex set of functions across the lifespan. To view this SnapShot, open or download the PDF.
The cerebrospinal fluid (CSF) has attracted renewed interest as an active signaling milieu that regulates brain development, homeostasis, and disease. Advances in proteomics research have enabled an ...improved characterization of the CSF from development through adulthood, and key neurogenic signaling pathways that are transmitted via the CSF are now being elucidated. Due to its immediate contact with neural stem cells in the developing and adult brain, the CSF’s ability to swiftly distribute signals across vast distances in the central nervous system is opening avenues to novel and exciting therapeutic approaches. In this review, we will discuss the development of the choroid plexus-CSF system, and review the current literature on how the CSF actively regulates mammalian brain development, behavior, and responses to traumatic brain injury.
Cerebral cortical progenitor cells can be classified into several different types, and each progenitor type integrates cell-intrinsic and cell-extrinsic cues to regulate neurogenesis. On one hand, ...cell-intrinsic mechanisms that depend upon appropriate apical-basal polarity are established by adherens junctions and apical complex proteins and are particularly important in progenitors with apical processes contacting the lateral ventricle. The apical protein complexes themselves are concentrated at the ventricular surface, and apical complex proteins regulate mitotic spindle orientation and cell fate. On the other hand, remarkably little is known about how cell-extrinsic cues signal to progenitors and couple with cell-intrinsic mechanisms to instruct neurogenesis. Recent research shows that the cerebrospinal fluid, which contacts apical progenitors at the ventricular surface and bathes the apical complex of these cells, provides growth- and survival-promoting cues for neural progenitor cells in developing and adult brain. This review addresses how the apical-basal polarity of progenitor cells regulates cell fate and allows progenitors to sample diffusible signals distributed by the cerebrospinal fluid. We also review several classes of signaling factors that the cerebrospinal fluid distributes to the developing brain to instruct neurogenesis.
Somatosensory over-reactivity is common among patients with autism spectrum disorders (ASDs) and is hypothesized to contribute to core ASD behaviors. However, effective treatments for sensory ...over-reactivity and ASDs are lacking. We found distinct somatosensory neuron pathophysiological mechanisms underlie tactile abnormalities in different ASD mouse models and contribute to some ASD-related behaviors. Developmental loss of ASD-associated genes Shank3 or Mecp2 in peripheral mechanosensory neurons leads to region-specific brain abnormalities, revealing links between developmental somatosensory over-reactivity and the genesis of aberrant behaviors. Moreover, acute treatment with a peripherally restricted GABAA receptor agonist that acts directly on mechanosensory neurons reduced tactile over-reactivity in six distinct ASD models. Chronic treatment of Mecp2 and Shank3 mutant mice improved body condition, some brain abnormalities, anxiety-like behaviors, and some social impairments but not memory impairments, motor deficits, or overgrooming. Our findings reveal a potential therapeutic strategy targeting peripheral mechanosensory neurons to treat tactile over-reactivity and select ASD-related behaviors.
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•Distinct pathophysiologies cause peripheral sensory neuron dysfunction in ASD models•Peripheral somatosensory neuron dysfunction alters brain development and behavior•A peripherally restricted GABAAR agonist, isoguvacine, reduces tactile sensitivity•Chronic isoguvacine treatment improves a subset of ASD-related phenotypes in mice
Treatment with a peripherally restricted GABAA receptor agonist in multiple distinct autism spectrum disorder mouse models reveals a potential therapeutic strategy for select ASD-related behaviors.
Choroid plexus (ChP) epithelial cells are crucial for the function of the blood-cerebrospinal fluid barrier (BCSFB) in the developing and mature brain. The ChP is considered the primary source and ...regulator of CSF, secreting many important factors that nourish the brain. It also performs CSF clearance functions including removing Amyloid beta and potassium. As such, the ChP is a promising target for gene and drug therapy for neurodevelopmental and neurological disorders in the central nervous system (CNS). This review describes the current successful and emerging experimental approaches for targeting ChP epithelial cells. We highlight methodological strategies to specifically target these cells for gain or loss of function in vivo. We cover both genetic models and viral gene delivery systems. Additionally, several lines of reporters to access the ChP epithelia are reviewed. Finally, we discuss exciting new approaches, such as chemical activation and transplantation of engineered ChP epithelial cells. We elaborate on fundamental functions of the ChP in secretion and clearance and outline experimental approaches paving the way to clinical applications.
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