Primary cilia maintain corneal epithelial homeostasis by regulation of the Notch signaling pathway

Abstract

Primary cilia have been linked to signaling pathways involved in cell proliferation, cell motility and cell polarity. Defects in ciliary function result in developmental abnormalities and multiple ciliopathies. Patients affected by severe ciliopathies such as Meckel syndrome, present several ocular surface disease conditions of unclear pathogenesis. Here we show that primary cilia are predominantly present on basal cells of the corneal epithelium (CE) throughout development and in adult. Conditional ablation of cilia in the CE leads to an increase in proliferation and vertical migration of basal corneal epithelial cells (CEC). A consequent increase in cell density of suprabasal layers results in a thicker than normal CE. Surprisingly, in cilia-deficient CE, cilia-mediated signaling pathways including Hh and Wnt were not affected but the intensity of Notch signaling was severely diminished. While NOTCH1 and NOTCH2 receptors were normally expressed, nuclear NOTCH1 Intracellular Domain (N1ICD) was severely reduced. Postnatal development analysis revealed that in cilia-deficient CEC downregulation of the Notch pathway precedes cell proliferation defects. Thus, we have uncovered a function of the primary cilium in maintaining homeostasis of the CE by balancing proliferation and vertical migration of basal CEC through modulation of Notch signaling.