Differential roles of FOXC2 in the trabecular meshwork and Schlemm’s canal in glaucomatous pathology

Naoto Ujiie, Pieter R. Norden, Raymond Fang, Lisa Beckmann, Zhen Cai, Junghun Kweon, Ting Liu, Can Tan, Megan S. Kuhn, W. Daniel Stamer, Kazushi Aoto, Susan E. Quaggin, Hao F. Zhang, Tsutomu Kume

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Impaired development and maintenance of Schlemm’s canal (SC) are associated with perturbed aqueous humor outflow and intraocular pressure. The angiopoietin (ANGPT)/TIE2 signaling pathway regulates SC development and maintenance, whereas the molecular mechanisms of crosstalk between SC and the neural crest (NC)-derived neighboring tissue, the trabecular meshwork (TM), are poorly understood. Here, we show NC-specific forkhead box (Fox)c2 deletion in mice results in impaired SC morphogenesis, loss of SC identity, and elevated intraocular pressure. Visible-light optical coherence tomography analysis further demonstrated functional impairment of the SC in response to changes in intraocular pressure in NC-Foxc2-/- mice, suggesting altered TM biomechanics. Single-cell RNA-sequencing analysis identified that this phenotype is predominately characterized by transcriptional changes associated with extracellular matrix organization and stiffness in TM cell clusters, including increased matrix metalloproteinase expression, which can cleave the TIE2 ectodomain to produce soluble TIE2. Moreover, endothelial-specific Foxc2 deletion impaired SC morphogenesis because of reduced TIE2 expression, which was rescued by deleting the TIE2 phosphatase VE-PTP. Thus, Foxc2 is critical in maintaining SC identity and morphogenesis via TM–SC crosstalk.

Original languageEnglish (US)
Article numbere202201721
JournalLife Science Alliance
Volume9
DOIs
StatePublished - Sep 2023
Externally publishedYes

ASJC Scopus subject areas

  • Ecology
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Plant Science
  • Health, Toxicology and Mutagenesis

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