Cell Junction Pathology of Neural Stem Cells Is Associated With Ventricular Zone Disruption, Hydrocephalus, and Abnormal Neurogenesis

Abstract

Fetal-onset hydrocephalus affects 1 to 3 per 1,000 live births. It is not only a disorder of cerebrospinal fluid dynamics but also a brain disorder that corrective surgery does not ameliorate. We hypothesized that cell junction abnormalities of neural stem cells (NSCs) lead to the inseparable phenomena of fetal-onset hydrocephalus and abnormal neurogenesis. We used bromodeoxyuridine labeling, immunocytochemistry, electron microscopy, and cell culture to study the telencephalon of hydrocephalic HTx rats and correlated our findings with those in human hydrocephalic and nonhydrocephalic human fetal brains (n = 12 each). Our results suggest that abnormal expression of the intercellular junction proteins N-cadherin and connexin-43 in NSC leads to 1) disruption of the ventricular and subventricular zones, loss of NSCs and neural progenitor cells; and 2) abnormalities in neurogenesis such as periventricular heterotopias and abnormal neuroblast migration. In HTx rats, the disrupted NSC and progenitor cells are shed into the cerebrospinal fluid and can be grown into neurospheres that display intercellular junction abnormalities similar to those of NSC of the disrupted ventricular zone; nevertheless, they maintain their potential for differentiating into neurons and glia. These NSCs can be used to investigate cellular and molecular mechanisms underlying this condition, thereby opening the avenue for stem cell therapy.

Neural Stem Cells and Fetal-Onset Hydrocephalus

“…1b) [22,50,51]. In the HTx mutant rat, disruption in the telencephalon starts at E19 and finishes at the 1st postnatal week [15]. In hydrocephalic fetuses, disruption of the VZ in the telencephalon has been shown as early as 16 GW.…”

“…Overall, a series of findings indicates that disruption of the VZ arises from a final common pathway involving alterations in vesicle trafficking, abnormal cell junctions, and loss of VZ integrity [19]. In brief, before becoming denuded, areas of the VZ display disorganized VZ/ependyma cells with an abnormal subcellular location of N-cadherin and connexin 43 [15,18,20,21]. Interestingly, specific domains of the ventricular walls that are permanently endowed with tight junctions, such as the subcommissural organ, choroid plexus and hypothalamic tanycytes never disrupt [22].…”

“…a-e' were taken from Guerra et al [15]. 455 from the caudal to rostral regions of the developing ventricular system.…”

“…3a, b, f). During the last few days of fetal life, the medial wall of the lateral ventricle of the rat is already lined by multiciliated ependyma, while the lateral and dorsal walls continue to be formed by NSC [15] (Fig. 2a, b, 3a-d).…”

“…Over the years, based on our own and other investigators' evidence, we have progressively come to the view that a disruption of the VZ and SVZ triggers onset of congenital hydrocephalus and abnormal neurogenesis [15,18]. The disruption process starts early in fetal life and finishes during the 1st postnatal weeks, affecting equally the NSC and the ependymal cells forming the VZ at preand postnatal stages of development (Fig.…”