June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Col4a1 mutations alter periocular mesenchyme cell migration that may contribute to anterior segment dysgenesis in mice.
Author Affiliations & Notes
  • Corinna Cozzitorto
    Ophthalmolgy, University of California San Francisco, San Francisco, California, United States
  • Zoe Peltz
    Ophthalmolgy, University of California San Francisco, San Francisco, California, United States
  • Lourdes Flores
    Ophthalmolgy, University of California San Francisco, San Francisco, California, United States
  • Mao Mao
    Ophthalmolgy, University of California San Francisco, San Francisco, California, United States
  • Luca Della Santina
    Ophthalmolgy, University of California San Francisco, San Francisco, California, United States
  • Douglas B Gould
    Ophthalmolgy, University of California San Francisco, San Francisco, California, United States
    Anatomy, University of California San Francisco, San Francisco, California, United States
  • Footnotes
    Commercial Relationships   Corinna Cozzitorto None; Zoe Peltz None; Lourdes Flores None; Mao Mao None; Luca Della Santina None; Douglas Gould None
  • Footnotes
    Support  NIH grant R01EY019887 for Douglas B. Gould
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 3586 – A0015. doi:
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      Corinna Cozzitorto, Zoe Peltz, Lourdes Flores, Mao Mao, Luca Della Santina, Douglas B Gould; Col4a1 mutations alter periocular mesenchyme cell migration that may contribute to anterior segment dysgenesis in mice.. Invest. Ophthalmol. Vis. Sci. 2022;63(7):3586 – A0015.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Mutations in collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) cause a multisystem disorder characterized by variable cerebrovascular, ocular, renal, and neuromuscular manifestations. The affected tissues are mainly derived from two distinct embryonic origins: the neural crest cells (NCCs) and the mesoderm germ layer. The periocular mesenchyme (POM) is a transient migratory embryonic tissue of NCCs and paraxial mesoderm derivation. It gives rise to anterior segment structures such as the corneal endothelium and stroma, trabecular meshwork, and ciliary muscle. Morphogenetic defects of these structures can impair aqueous humor outflow, leading to elevated intraocular pressure and glaucoma development. Approximately one-third of patients with COL4A1 and COL4A2 mutations have ocular anterior segment dysgenesis (ASD), including congenital glaucoma resulting from dysgenesis of POM-derived structures. POM terminal differentiation has been the major focus of ASD research, but the cellular mechanisms are still unclear. We hypothesize that Col4a1 mutation may alter POM biology underlying ASD.

Methods : Immunofluorescence and confocal microscopy were performed on control and Col4a1 mutant mouse embryos at embryonic day (E) 9.5 and E10.5 using antibodies against SOX10 to label migratory NCCs, and FOXC1 and PITX2 to label the POM and prospective corneal stroma at E12.5.

Results : SOX10 labeling revealed that Col4a1 mutant and control embryos had similar numbers of migrating cranial NCCs at both E9.5 and E10.5. However, compared to control littermates, cranial NCCs moving towards the eye region in E9.5 mutants showed abnormal migration, forming a less cohesive migratory stream. On the other hand, within the POM of E9.5 and E10.5 Col4a1 mutant embryos, NCCs clustered more closely. POM analysis at E12.5 revealed that FOXC1+, but not PITX2+, POM cells migrate less cohesively within the prospective corneal stroma of Col4a1 mutant embryos compared to controls.

Conclusions : In agreement with our hypothesis, our results show for the first time that Col4a1 mutations lead to cranial NCC and POM migratory defects without affecting cell numbers. Further examinations are needed to understand both the molecular causes and consequences of the uncovered migratory phenotype. Future work will analyze the mesodermal contribution to ASD in Col4a1 mutants.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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