Abstract
Adherens junctions (AJs) play a role in mechanically connecting adjacent cells to maintain tissue structure, particularly in epithelial cells. The major cell–cell adhesion molecules at AJs are cadherins and nectins. Afadin binds to both nectins and α-catenin and recruits the cadherin-β-catenin complex to the nectin-based cell–cell adhesion site to form AJs. To explore the role of afadin in radial glial and ependymal cells in the brain, we generated mice carrying a nestin-Cre-mediated conditional knockout (cKO) of the afadin gene. Newborn afadin-cKO mice developed hydrocephalus and died neonatally. The afadin-cKO brain displayed enlarged lateral ventricles and cerebral aqueduct, resulting from stenosis of the caudal end of the cerebral aqueduct and obliteration of the ventral part of the third ventricle. Afadin deficiency further caused the loss of ependymal cells from the ventricular and aqueductal surfaces. During development, radial glial cells, which terminally differentiate into ependymal cells, scattered from the ventricular zone and were replaced by neurons that eventually covered the ventricular and aqueductal surfaces of the afadin-cKO midbrain. Moreover, the denuded ependymal cells were only occasionally observed in the third ventricle and the cerebral aqueduct of the afadin-cKO midbrain. Afadin was co-localized with nectin-1 and N-cadherin at AJs of radial glial and ependymal cells in the control midbrain, but these proteins were not concentrated at AJs in the afadin-cKO midbrain. Thus, the defects in the afadin-cKO midbrain most likely resulted from the destruction of AJs, because AJs in the midbrain were already established before afadin was genetically deleted. These results indicate that afadin is essential for the maintenance of AJs in radial glial and ependymal cells in the midbrain and is required for normal morphogenesis of the cerebral aqueduct and ventral third ventricle in the midbrain.
Highlights
The aqueductal and ventricular walls of the brain are covered by a succession of epithelial cells, progressing from neuroepithelial to radial glial and eventually ependymal cells, over the course of development [1,2]
Because the apical surface of the lateral ventricles is covered by radial glial cells until around E15 and covered by ependymal cells that are produced from radial glial cells between E14 and E16 [42], and N-cadherin and nectin-1 are major cell adhesion molecules (CAMs) at adherens junctions (AJs) in the nervous tissues [44,45], these results indicate that afadin is localized at AJs in radial glial and ependymal cells at the cerebral aqueduct and the third ventricle
To clarify the role of afadin in the development of the central nervous system (CNS), we generated the nestin-Cre-mediated conditional knockout (cKO) mice of the afadin gene and showed here that the genetic deletion of afadin in the brain caused hydrocephalus with stenosis of the cerebral aqueduct and obliteration of the ventral part of the third ventricle
Summary
The aqueductal and ventricular walls of the brain are covered by a succession of epithelial cells, progressing from neuroepithelial to radial glial and eventually ependymal cells, over the course of development [1,2]. These epithelial cells attach to each other via a junctional complex of adherens junctions (AJs) and tight junctions (TJs) to form a monolayer sheet. TJs are developed in addition to AJs in epithelial and endothelial cells, including neuroepithelial and ependymal cells, but not in radial glial cells [2,4]. The formation and maintenance of TJs are regulated by AJs [6]
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