Yap is required for ependymal integrity and is suppressed in LPA-induced hydrocephalus.

Raehee Park,Jun Young Park,Randy L Johnson,Seonhee Kim,Seo-Hee Cho,Uk Yeol Moon,Lucinda J Hughes

doi:10.1038/ncomms10329

Abstract

Timely generation and normal maturation of ependymal cells along the aqueduct are critical for preventing physical blockage between the third and fourth ventricles and the development of fetal non-communicating hydrocephalus. Our study identifies Yap, the downstream effector of the evolutionarily conserved Hippo pathway, as a central regulator for generating developmentally controlled ependymal cells along the ventricular lining of the aqueduct. Yap function is necessary for proper proliferation of progenitors and apical attachment of ependymal precursor cells. Importantly, an injury signal initiated by lysophosphatidic acid (LPA), an upstream regulator of Yap that can cause fetal haemorrhagic hydrocephalus, deregulates Yap in the developing aqueduct. LPA exposure leads to the loss of N-cadherin concentrations at the apical endfeet, which can be partially restored by forced Yap expression and more efficiently by phosphomimetic Yap. These results reveal a novel function of Yap in retaining tissue junctions during normal development and after fetal brain injury.

Highlights

Generation and normal maturation of ependymal cells along the aqueduct are critical for preventing physical blockage between the third and fourth ventricles and the development of fetal non-communicating hydrocephalus
Yap is highly expressed in the developing nervous system and acts as a downstream effector of NF2, regulating neural progenitor proliferation in the hippocampus[15]
In contrast to wild type (WT), dye failed to reach the fourth ventricle at P0, P3 (Supplementary Fig. 1) and P5 (Fig. 1b), providing direct evidence for physical blockage of the aqueduct and resulting noncommunicating hydrocephalus

Summary

Introduction

Generation and normal maturation of ependymal cells along the aqueduct are critical for preventing physical blockage between the third and fourth ventricles and the development of fetal non-communicating hydrocephalus. Our study identifies Yap, the downstream effector of the evolutionarily conserved Hippo pathway, as a central regulator for generating developmentally controlled ependymal cells along the ventricular lining of the aqueduct. Failure of normal generation, maturation and integrity of ependymal cells can cause early onset fetal hydrocephalus through aqueductal stenosis, which blocks CSF in the narrow passage between the third and fourth ventricles[3,8]. Our results demonstrate a novel function of cytoplasmic/ junctional Yap in establishing and maintaining cellular and tissue integrity by supporting junction protein localization during normal development and after fetal brain injury

Methods

Results

Conclusion