Primary cilia maintain corneal epithelial homeostasis by regulation of the Notch signaling pathway
Open accessAbstract
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.
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Primary cilia act as sensory structures that regulate diverse signaling pathways essential for development and homeostasis.
“They act as sensory structures that regulate diverse signaling pathways essential for development and homeostasis [10,11].”
From The Impact of Neurotoxin Proteins Trafficked by Primary Cilia and Extracellular Vesicles in Neurodegenerative Diseases (2025) · cites this paper as [10]
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Signaling through the Primary Cilium
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Primary cilia: Structure, dynamics, and roles in cancer cells and tumor microenvironment
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Kaplan, N., Wang, S., Wang, J., Yang, W., Ventrella, R., Majekodunmi, A., White, B. E. P., Getsios, S., Mitchell, B. J., Peng, H., et al. (2021) · The Ocular Surface · doi:10.1016/j.jtos.2021.06.006 · Cited by 14 · see citing works
Cutaneous findings in Bardet‐Biedl syndrome
Haws, R. M., McIntee, T. J., & Green, C. B. (2019) · International Journal of Dermatology · doi:10.1111/ijd.14412 · Cited by 14 · see citing works
Portal, C., Wang, Z., Scott, D. K., Wolosin, J. M., & Iomini, C. (2022) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.63.2.3 · Cited by 13 · see citing works
Self-citationKong, D., Wei, M., Liu, D., Zhang, Z., Ma, Y., & Zhang, Z. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241411537 · Cited by 12 · see citing works
Clinical Implications of Primary Cilia in Skin Cancer
Choudhury, A., Neumann, N. M., Raleigh, D. R., & Lang, U. E. (2020) · Dermatology and Therapy · doi:10.1007/s13555-020-00355-1 · Cited by 10 · see citing works
Regulation of Primary Cilium Length by O-GlcNAc during Neuronal Development in a Human Neuron Model
Tian, J. L., Huang, C., Eslami, F., Mannino, M. P., Lee, R., & Hart, G. W. (2023) · Cells · doi:10.3390/cells12111520 · Cited by 12 · see citing works
Paulson, D., Harms, R., Ward, C., Latterell, M., Pazour, G. J., & Fink, D. M. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.672625 · Cited by 11 · see citing works
“Primary cilia house receptor-ligand signaling pathways such as Hedgehog (Huangfu et al., 2003; Huangfu and Anderson, 2005; Clement et al., 2009), Wnt (Jonassen et al., 2008; McDermott et al., 2010), Notch (Ezratty et al., 2011; Grisanti et al., 2016; Chen et al., 2017), PDGFRα (Schneider et al., 2005; Noda et al., 201…”
Munch, T. N., Hedley, P. L., Hagen, C. M., Bækvad‐Hansen, M., Geller, F., Bybjerg‐Grauholm, J., Nordentoft, M., Børglum, A. D., Werge, T. M., Melbye, M., et al. (2022) · Brain Communications · doi:10.1093/braincomms/fcad004 · Cited by 11 · see citing works
Microstructure characteristics of cornea of some birds: a comparative study
Abdelftah, Z., Gaber, A. R., Abo‐Eleneen, R. E., & El-Bakry, A. M. (2021) · Beni-Suef University Journal of Basic and Applied Sciences · doi:10.1186/s43088-021-00155-2 · Cited by 10 · see citing works
Bex1 is essential for ciliogenesis and harbours biomolecular condensate-forming capacity
Hibino, E., Ichiyama, Y., Tsukamura, A., Senju, Y., Morimune, T., Ohji, M., Maruo, Y., Nishimura, M., & Mori, M. (2022) · BMC Biology · doi:10.1186/s12915-022-01246-x · Cited by 10 · see citing works
“In the cornea, primary cilia control the proliferation of corneal epithelial [62] and endothelial [63] cells during corneal development.”
BackgroundGenome‐wide association studies for iris pigmentation and heterochromia patterns in Large White pigs
Moscatelli, G., Bovo, S., Schiavo, G., Mazzoni, G., Bertolini, F., Dall’Olio, S., & Fontanesi, L. (2020) · Animal Genetics · doi:10.1111/age.12930 · Cited by 8 · see citing works
Notch1 signaling in keratocytes maintains corneal transparency by suppressing VEGF expression
Biswas, S., Shafiquzzaman, M., Yu, G., Li, P., Yu, Q., Zhao, P., Li, B., & Li, J. (2022) · Stem Cell Reports · doi:10.1016/j.stemcr.2022.04.017 · Cited by 8 · see citing works
“Previous studies suggest that Notch1 signaling plays critical roles in corneal development (Grisanti et al., 2016; Pang et al., 2021).”
ResultThe role of the primary cilium in cancer
Cao, H., Liu, M.-M., Shao, Q.-N., & Jiao, Z.-Y. (2021) · Neoplasma · doi:10.4149/neo_2021_210210n204 · Cited by 8 · see citing works
The implication of ciliary signaling pathways for epithelial–mesenchymal transition
Zhong, B., & Dong, M. (2023) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-023-04817-w · Cited by 8 · see citing works
“Loss of primary cilium in corneal epithelial diminished NOTCH activation to reduce cell proliferation, accompanied by NOCTH1 and NOTCH2 receptors which were normally expressed and nuclear NOTCH1 Intracellular Domain (NICD1) was severely reduced [77].”
BackgroundPortal, C., Lin, Y. G., Rastogi, V., Peterson, C., Yiu, S. C., Foster, J. W., Wilkerson, A., Butovich, I. A., & Iomini, C. (2023) · Communications Biology · doi:10.1038/s42003-023-04632-5 · Cited by 6 · see citing works
Self-citationThe role of primary cilia in thyroid diseases
Tian, Z., Li, X., Yu, X. L., Yan, S., Sun, J., Ma, W., Zhu, X., & Tang, Y. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1306550 · Cited by 6 · see citing works
Ye, J., Sheahon, K. M., LeBoit, P. E., McCalmont, T. H., & Lang, U. E. (2021) · Journal of Cutaneous Pathology · doi:10.1111/cup.14073 · Cited by 6 · see citing works
“downstream effector molecules, including those of the Hedgehog, PDGF, Wnt, and Notch pathways, having been shown to localize to the ciliary membrane, which is an extension of the cell membrane.(28-31)”
YIN, H., WANG, L., Fan, Y., & Fu, B. M. (2021) · Biocell · doi:10.32604/biocell.2021.016650 · Cited by 6 · see citing works
Bräutigam, K., Reinhard, S., Galván, J. A., Wartenberg, M., Hewer, E., & Schürch, C. M. (2022) · Respiration · doi:10.1159/000521317 · Cited by 5 · see citing works
Munch, T. N., Hedley, P. L., Nielsen, K. G., Christiansen, M., & Jurisch‐Yaksi, N. (2025) · Journal of Molecular Neuroscience · doi:10.1007/s12031-025-02405-9 · Cited by 4 · see citing works
“NOTCH2 , which encodes the notch receptor 2, has been associated with human hydrocephalus (Furey et al. 2018a; Fiddes et al. 2018; Grisanti et al. 2016), which may be part of the rare Hajdu-Cheney syndrome (Johnson and O’Neill 2020).”
Ni, H., Li, L., Hu, D., Yang, M., Wang, D., Ma, H., Bu, W., Yang, J., Zhu, L., Zhai, D., et al. (2024) · Journal of Cellular Physiology · doi:10.1002/jcp.31215 · Cited by 3 · see citing works
“In mice, ciliary formation is synchronized with corneal epithelial development, and depletion of cilia induces abnormal thickening of the corneal epithelium and structural abnormalities by reducing Notch signaling (Grisanti et al., 2016).”
BackgroundInfluentialSalzmann's nodular degeneration in a patient with Kartagener syndrome
Dugauquier, A., Schrooyen, M., & Cordonnier, M. (2020) · Journal Français d Ophtalmologie · doi:10.1016/j.jfo.2020.05.011 · Cited by 2 · see citing works
Primary cilium and its role in tumorigenesis
Hongmei, M. A. O., & Sun, Y. (2021) · Journal of Zhejiang University (Medical Sciences) · doi:10.3724/zdxbyxb-2021-0048 · Cited by 2 · see citing works
“常以及表皮发育过程中基底细胞向棘细胞分化异 常[19]。后续研究表明表皮层中Notch信号通路的活 性与原纤毛也是相关的[142]。另外,Grisanti等[143]发 现角膜上皮细胞原纤毛的缺失会降低Notch信号 通路的活性,导致细胞核内NICD含量降低从而减”
BackgroundThe role of cilia in the development, survival, and regeneration of hair cells
Boldizar, H., Friedman, A. E., Stanley, T., Padilla, M., Galdieri, J., Sclar, A., & Stawicki, T. M. (2024) · Biology Open · doi:10.1242/bio.061690 · Cited by 2 · see citing works
“Cilia have also been shown to be important for normal notch signaling in epidermal keratinocytes, corneal epithelium cells, and hematopoietic stem and progenitor cells (Ezratty et al., 2011; Grisanti et al., 2016; Liu et al., 2019).”
BackgroundSHIRAKAWA, K., Nakazato, R., Hara, T., Uemura, K., Ijaz, F., Takahashi, S., & Ikegami, K. (2025) · Medical Molecular Morphology · doi:10.1007/s00795-025-00428-0 · Cited by 2 · see citing works
Hedgehog pathway activity downstream of Smoothened is regulated specifically by basal ciliary PKA
Zhang, H., Chen, S., Huang, Z., Ben, J., Wei, Y., Chen, G., Wu, C., Xie, H., Ingham, P. W., & Zhao, Z. (2026) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-026-00915-x · Cited by 2 · see citing works
May‐Simera, H., Wan, Q., Jha, B. S., Hartford, J., Khristov, V., Dejene, R., Chang, J., Patnaik, S. R., Lü, Q., Banerjee, P., et al. (2018) · SSRN Electronic Journal · doi:10.2139/ssrn.3155914 · Cited by 2 · see citing works
Danna, R., Kondle, S., Amar, O., Mabourakh, M., Chen, G., Fadol, W. B., & Mohieldin, A. M. (2025) · Biology · doi:10.3390/biology14121787 · Cited by 2 · see citing works
Cell-lineage specificity of primary cilia during epididymis post-natal developmentPreprint
Bernet, A., Bastien, A., Soulet, D., Jerczynski, O., Roy, C., Alves, M. B. R., Lecours, C., Tremblay, M., Bailey, J. L., Robert, C., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/288977
Aniridia-related keratopathy : structural changes, signaling pathways and clinical aspects
Vicente, A. (2019) · DiVA at Umeå University (Umeå University)
Portal, C., Lin, Y. G., Rastogi, V., Peterson, C., Foster, J. W., Wilkerson, A., Butovich, I. A., & Iomini, C. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.16.492188
“As previously published, no evident defects were visible in newborn cKO mice and eyelid opening occurs around P13 in both control and cKO mice (Croyle et al., 2011; Grisanti et al., 2016).”
BackgroundSelf-citationMelo-Escobar, M. I. (2022) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/d.42.2022.tde-22082023-084314
zhang, Z., He, J., Zhu, Y., & He, W. (2023) · Research Square · doi:10.21203/rs.3.rs-3505942/v1
Kong, D., Zhang, L., Lai, W., Zhang, Z., & Zhang, Z. (2024) · SSRN Electronic Journal · doi:10.2139/ssrn.4795612
Refractive errors in patients with Bardet Biedl syndrome
Saricay, L. Y., Baldwin, G. E., Moulton, E. A., Gonzalez, J. E., Rajabi, F., Hunter, D. G., & Fulton, A. B. (2024) · Ophthalmic Genetics · doi:10.1080/13816810.2024.2357296
Guo, Y., He, X., Liu, J., Tan, Y., Zhang, C., Chen, S., & Zhang, S. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2024.1495753
Role of Primary Cilia in the Eye
Reichert, D., Sharma, R., May‐Simera, H., & Bharti, K. (2025) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-76550-6_72 · Cited by 1 · see citing works
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Bex1 is essential for ciliogenesis and harbours biomolecular condensate-forming capacity.
日比野, 絵., Ichiyama, Y., 塚村, 篤., 森宗, 孝., 大路, 正., 丸尾, 良., 西村, 正., 森, 雅., Hibino, E., Tsukamura, A., et al. (n.d.) · Institutional Repositories DataBase (IRDB)
Primary cilium disassembly – from mechanisms to roles in physiology and disease
Ott, C. M., Lippincott‐Schwartz, J., & Breslow, D. K. (2026) · Journal of Cell Science · doi:10.1242/jcs.264820
“For example, in epithelial wound-healing assays, disassembly occurs in the cells adjacent to the wound that migrate to fill the gap (Grisanti et al., 2016).”
Modulation of Cilia Motility by Vortex-Ultrasound-Induced Shear Stress
Phan, T.-N., Wang, H.-C., Fan, C.-H., Huang, C.-H., Fang, Y., Luo, Y., Ma, Z., Lin, I.-H., Wang, W.-J., Lin, Y.-C., et al. (2026) · ACS Nano · doi:10.1021/acsnano.6c06231
- Authors
- Grisanti, L., Revenkova, E., Gordon, R. E., & Iomini, C.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Iomini, Carlo
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2016-01-01
- Volume
- 143
- Issue
- 12
- Pages
- 2160-71
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- PMC
- PMC4920172
- OpenAlex
- W2345231977
- Cited by
- 71
- References
- 53
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 5 · 2023: 8 · 2022: 9 · 2021: 9 · 2020: 10 · 2019: 8 · 2018: 9 · 2017: 4 · 2016: 2
- FWCI
- 6.19
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Eye Institute (EY022639)
- Research to Prevent Blindness (Dolly Green Special Scholar Award, Unrestricted Grant)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Ocular Disorders and Treatments
- Keywords
- primary cilia, corneal epithelium, Notch signaling, Notch1, Notch2, ciliopathies, Meckel syndrome, ocular surface disease, basal epithelial cells, cell proliferation, vertical migration, corneal epithelial homeostasis, corneal thickness
- MeSH terms
- Animals, Animals, Newborn, Cell Movement, Cilia, Epithelial Cells, Homeostasis, Mice, Inbred C57BL, Mutation, Wound Healing, Signal Transduction, Mice, Knockout, Epithelium, Corneal, Tumor Suppressor Proteins, Cell Proliferation, Receptor, Notch1, Receptor, Notch2
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