Molecular hallmarks of hydrocephalus
Andrew T. Hale, Blake Zhou, Arjun Rajan, Phan Q. Duy, Mubeen Goolam, Seth L. Alper, Maria K. Lehtinen, Madeline A. Lancaster, Ryann M. Fame, Kristopher T. Kahle
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.