The investigation of hydrocephalus in mice lacking the transcription factor NFIX

Abstract

Hydrocephalus is a relatively common birth defect (Bruni, Del Bigio, & Clattenburg, 1985) but despite its prevalence, and the existence of several rodent models of this disorder (Jones & Bucknall, 1988; K. Lee et al., 2012; Perez-Figares et al., 1998), our understanding of the molecular and cellular mechanisms leading to the pathological cerebrospinal fluid (CSF) accumulation remains limited. This thesis has focused on investigating hydrocephalus in mice lacking Nuclear factor one X (NFIX). NFIX belongs to a group of site-specific transcription factors known as the Nuclear factor one gene (NFI) family. Preliminary data in mouse models has shown that NFIX is expressed by neural progenitor cells within the central nervous system (CNS) and that mice lacking this gene exhibit abnormal phenotypes within the rodent developing forebrain. Here we revealed that hydrocephalus is a consistent feature present in mice lacking the transcription factor Nfix, implicating normal NFIX function as being central to the formation of the intraventricular region of the central nervous system. Specifically, we have demonstrated that NFIX is central to the biology of ependymal cells, and that in its absence, the lateral ventricles of the dorsal telencephalon exhibit denudation of the ependymal cell layer. We have shown that Nfix deficient mice exhibit aberrant ependymal cell morphology at postnatal day (P) 15, culminating in abnormal thickening and sloughing of this cellular layer. Moreover, we showed that the expression of ependymal cell-specific markers was delayed. Finally, we revealed Foxj1, a key factor promoting ependymal cell maturation, as a target for NFIX-mediated transcriptional activation. Collectively, our data suggested that ependymal cell development may be reliant, at least in part, on NFIX expression, implicating this transcription factor as a mediator of ependymal cell biology. Owing to our limited knowledge of the genetics and molecular pathogenesis of human hydrocephalus, using data extrapolated from animal models may provide invaluable information regarding the development of this disease in humans. This may prove useful when considering strategies to harness better treatments, such as drug-based therapeutics, to treat patients with hydrocephalus and, to improve early diagnosis of this disorder. Therefore a better understanding of the pathogenesis and the underlying causes leading to the development of hydrocephalus are necessary.