Yap1 is required for maintenance of adult RPE differentiation

Area of Science:

• Cell Biology
• Ophthalmology
• Developmental Biology

Background:

• Nuclear YAP1 regulates stem cell proliferation and tissue regeneration.
• The cytoplasmic role of YAP1 in epithelial cells is less understood due to rapid cell turnover.
• The retinal pigment epithelium (RPE) is a polarized, senescent epithelial model ideal for studying adult YAP1 function.

Purpose of the Study:

• To investigate the essential role of cytoplasmic YAP1 in maintaining adult RPE differentiation and function.
• To elucidate the molecular mechanisms by which YAP1 influences RPE phenotype and prevents dedifferentiation.

Main Methods:

• Adult mouse RPE-specific Yap1 knockout model.
• Analysis of RPE cell morphology, tight junctions, and pigment content.
• Assessment of photoreceptor integrity and visual function.
• Evaluation of nuclear beta-catenin levels and Wnt/beta-catenin signaling activity.

Main Results:

• Yap1 knockout in adult RPE caused cell depolarization, tight junction loss, and reduced RPE65 expression.
• RPE dedifferentiation included pigment diminishment and structural changes (microvilli, basal infoldings).
• RPE defects led to photoreceptor outer segment loss, photoreceptor death, and age-dependent vision decline.
• Increased nuclear beta-catenin and activity were observed in mutant RPE, indicating Wnt/beta-catenin pathway activation.

Conclusions:

• Cytoplasmic YAP1 is essential for maintaining adult RPE differentiation and preventing dedifferentiation.
• YAP1 actively inhibits Wnt/beta-catenin signaling, crucial for preserving RPE phenotype.
• Dysregulation of YAP1 in RPE contributes to age-related vision impairment and photoreceptor degeneration.