143 Elucidating the Function of the Wnt Signaling Pathway in Hydrocephalus

Abstract

INTRODUCTION: Although acquired hydrocephalus is commonly encountered by neurosurgeons, our understanding of the mechanisms underlying its pathogenesis remain poor. Furthermore, normal CSF physiology is dependent on the proper function of ventricular ependymal cells and choroid plexus epithelium (CPE), although few neurosurgical studies have addressed the functions of these cells. METHODS: Alteration of the Wnt pathway is achieved by generating FoxJ1-Cre;Apclox/lox and FoxJ1-Cre;Ctnnb1lox/lox mice, which express Cre upon induction with tamoxifen, as well as via intraventricular delivery of an AAV1-eGFP-Cre in Apclox/lox and Ctnnb1lox/lox mice. T2 weighted MRI with 3D volumetrics is applied to assess ventricular anatomy, in addition to standard molecular biology techniques to examine downstream signaling mechanisms. Kaolin and whole blood injection are used as models of obstructive and communicating hydrocephalus, respectively. RESULTS: B-catenin is strongly expressed in adult mouse ependyma and CPE, suggesting that the canonical Wnt pathway continues to be active after these cells have developed. Moreover, up-regulation of this pathway in adult FoxJ1-Cre;Apclox/lox mice results in significant ventricular enlargement (n = 3; p = 0.03). Both FoxJ1-Cre transgenic mice and intraventricular AAV1-eGFP-Cre drive selective expression within ependyma and CPE, suggesting that these may be useful models for investigating important molecular pathways within these cells. CONCLUSIONS: Our data suggests that the canonical Wnt signaling pathway plays a role in the maintenance of normal adult CSF dynamics. Moreover, we show selective targeting of ependyma and CPE using an adeno-associated virus, which may represent a novel strategy for modifying genes and/or proteins involved in CSF regulation.