De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus

Congenital hydrocephalus (CH), featuring markedly enlarged brain ventricles, is thought to arise from failed cerebrospinal fluid (CSF) homeostasis and is treated with lifelong surgical CSF shunting with substantial morbidity. CH pathogenesis is poorly understood. Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 × 10−7), SMARCC1 (p = 8.15 × 10−10), and PTCH1 (p = 1.06 × 10−6). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 × 10−4). Together, these probands account for ∼10% of studied cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate. These results implicate impaired neurogenesis (rather than active CSF accumulation) in the pathogenesis of a subset of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications

Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH

Cellular signaling in neural stem cells: implications for restorative neurosurgery

Over the course of the past few decades, it has become apparent that in contrast to previously held beliefs, the adult central nervous system (CNS) may have the capability of regeneration and repair. This greatly expands the possibilities for the future treatment of CNS disorders, with the potential strategies of treatment targeting the entire scope of neurological diseases. Indeed, there is now ample evidence that stem cells exist in the CNS throughout life, and the progeny of these stem cells may have the ability to assume the functional role of neural cells that have been lost. The existence of stem cells is no longer in dispute. In addition, once transplanted, stem cells have been shown to survive, migrate, and differentiate. Nevertheless, the clinical utility of stem cell therapy for neurorestoration remains elusive. Without question, the control of the behavior of stem cells for therapeutic advantage poses considerable challenges. In this paper, the authors discuss the cellular signaling processes that influence the behavior of stem cells. These signaling processes take place in the microenvironment of the stem cell known as the niche. Also considered are the implications attending the replication and manipulation of elements of the stem cell niche to restore function in the CNS by using stem cell therapy