Molecular hallmarks of hydrocephalus

Abstract

Hydrocephalus (HC) is a failure of brain and cerebrospinal fluid (CSF) homeostasis often associated with dilation of the CSF-filled ventricles (ventriculomegaly). Hallmarks of HC include aberrant CSF dynamics, neural stem cell dysfunction resulting in impaired neurogenesis and corticogenesis, biomechanical instability at the brain-CSF interface, and disrupted synaptogenesis and neural circuitry. Pleiotropic mechanisms, including genetic and environmental insults to the brain, contribute to neurodevelopmental comorbidities. Hypothesis generation from genome-wide, single-cell multi-omic analyses coupled to experimental validation using induced pluripotent stem cell-derived cerebral organoids will refine molecular classification of HC subtypes and may lead to precision-based surgical and pharmacologic treatments.

Figure 1.. Overview of the human cerebroventricular system.

(A) Illustration of the choroid plexus (ChP) epithelium with component cell types. (B) Systemic movement of cerebrospinal fluid (CSF) produced by the ChP epithelium. CSF is thought to traverse the subarachnoid space and to be reabsorbed into the systemic circulation via the arachnoid granulations (B) or the cranial meninges and the glymphatic system (C). Abbreviations: aqueduct of Sylvius (AS), cerebrospinal fluid (CSF), ChP (CP), foramen of Monro (FM), foramen of Luschka (FM), fourth ventricle (4V), lateral ventricle (LV), interstitial fluid (ISF), third ventricle (3V), and subventricular zone (SVZ).

Figure 2.. The hallmarks of human hydrocephalus,

defined as neural stem cell (NSC) dysfunction, alterations in corticogenesis, brain volume and growth perturbation, biomechanical disruption, defects in synaptogenesis and brain circuitry, aberrant cerebrospinal fluid dynamics and choroid plexus development, genetic predisposition, and ventriculomegaly and comorbid traits.

Figure 3.

Overview of human neocortical development and HC-associated genes. (A) Cellular differentiation during cortical development between gestational weeks (GW) 4–40. NSCs successively expand, generate progenitors, and differentiate to form the principal components of the human cortex and ventricular system ^, . (B) Summary of cell types and their HC-associated gene expression. (C) UMAP clustering of HC-associated gene expression in neural progenitor cells (RGCs, oRGCs, IPCs, ORGs) and early differentiated neural cell types during human brain development. Processed scRNA-seq data of human neocortical samples was obtained from Wang, et al. 2024 . The data subset was of cells originating from pre-natal samples (including first, second, and third trimester). Cell types were re-annotated to reflect stages of neural differentiation by combining annotated cell-types from the original publication using SCANPY . Expression values reflect log normalized UMI counts with a size factor of 10,000. Known markers of the annotated cell types (PAX6, TBR2, NeuN, GFAP) are plotted to demonstrate annotation specificity, and are compared with expression plots of 10 HC-linked genes.