Primary cilia maintain corneal epithelial homeostasis by regulation of the Notch signaling pathway.
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 mouse corneal epithelium (CE) throughout development and in the adult. Conditional ablation of cilia in the CE leads to an increase in proliferation and vertical migration of basal corneal epithelial cells (CECs). 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 pathways, were not affected but the intensity of Notch signaling was severely diminished. Although Notch1 and Notch2 receptors were expressed normally, nuclear Notch1 intracellular domain (N1ICD) expression was severely reduced. Postnatal development analysis revealed that in cilia-deficient CECs 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 CECs through modulation of Notch signaling.
Department of Ophthalmology and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
Laura
L
Grisanti
Department of Ophthalmology and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
Ekaterina
E
Revenkova
Department of Pathology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
Ronald E
RE
Gordon
Department of Ophthalmology and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA carlo.iomini@mssm.edu.
Carlo
0000-0001-6483-9540
C
Iomini
D000818:Animals; D000831:Animals, Newborn; D002465:Cell Movement; D049109:Cell Proliferation; D002923:Cilia / Q000378:metabolism* / Q000648:ultrastructure; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D019573:Epithelium, Corneal / Q000378:metabolism* / Q000648:ultrastructure; D006706:Homeostasis; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D051881:Receptor, Notch1 / Q000378:metabolism*; D051883:Receptor, Notch2 / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014945:Wound Healing
D051881:Receptor, Notch1; D051883:Receptor, Notch2; C490898:Tg737Rpw protein, mouse; D025521:Tumor Suppressor Proteins
Cornea; Epithelium; Mouse; Notch signaling; Ocular surface; Primary cilia; Wound healing