Genetic deletion of afadin causes hydrocephalus by destruction of adherens junctions in radial glial and ependymal cells in the midbrain.
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.
Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan ; Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan ; CREST, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan.
Hideaki
H
Yamamoto
Tomohiko
T
Maruo
Takashi
T
Majima
Hiroyoshi
H
Ishizaki
Miki
M
Tanaka-Okamoto
Jun
J
Miyoshi
Kenji
K
Mandai
Yoshimi
Y
Takai
D022005:Adherens Junctions / Q000473:pathology*; D000818:Animals; D002535:Cerebral Aqueduct / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D063928:Ependymoglial Cells / Q000378:metabolism* / Q000473:pathology*; D017353:Gene Deletion; D006849:Hydrocephalus / Q000235:genetics* / Q000473:pathology*; D008636:Mesencephalon / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D021381:Protein Transport; D020542:Third Ventricle / Q000378:metabolism / Q000473:pathology
D008840:Microfilament Proteins; C108835:afadin