Genetic Regulation of Wnt/PCP Components Through Fgf10/Fgfr2/Sox9 Module in Tear Duct Development.

Area of Science:

• Developmental Biology
• Molecular Genetics
• Ophthalmology

Background:

• Tear duct obstruction can cause ocular surface disorders.
• Fgf signaling is implicated in congenital tear duct obstruction, but its regulatory networks are not fully understood.
• Investigating the interplay between Fgf and Wnt/planar cell polarity (PCP) pathways is essential for understanding tear drainage system development.

Purpose of the Study:

• To elucidate the developmental biology and molecular genetics of the tear drainage system.
• To investigate genetic interactions between the Fgf and Wnt/PCP pathways in tear duct formation.

Main Methods:

• Generation of mutant mice with disruptions in Fgf10, Fgfr2, or Sox9.
• Analysis of tear duct development using immunohistochemistry and in situ hybridization.
• Single-cell RNA sequencing, CUT&Tag analysis, luciferase reporter assays, and electrophoretic mobility shift assays (EMSA) to identify gene targets and interactions.

Main Results:

• Fgf10 and Fgfr2 are essential for tear duct formation by regulating progenitor cell proliferation and survival.
• The Fgf10/Fgfr2/Sox9 module controls Wnt/PCP genes involved in embryonic tear duct elongation.
• Sox9 directly activates the promoter of Prickle1, a Wnt/PCP component, and Fgf signaling acts unidirectionally on Wnt/PCP components.

Conclusions:

• A direct genetic link between Fgf signaling and the Wnt/PCP pathway in tear duct formation has been uncovered.
• Wnt/PCP pathway components may represent potential risk factors for congenital nasolacrimal duct obstruction (CNLDO).
• Further investigation into the role of Wnt/PCP components in CNLDO is warranted.