YAP controls retinal stem cell DNA replication timing and genomic stability.

Area of Science:

• Stem cell biology
• Developmental biology
• Molecular genetics

Background:

• Adult frog retinas possess neural stem cells crucial for lifelong eye growth.
• The Hippo pathway's role and its effectors in stem cell regulation are areas of active investigation.

Purpose of the Study:

• To investigate the function of Yap, a Hippo pathway effector, in adult retinal stem cells.
• To elucidate the molecular mechanisms by which Yap influences DNA replication and genomic stability in these cells.

Main Methods:

• Yap gene knockdown in adult frog retinal stem cells.
• Analysis of DNA replication progression (S-phase) and cell cycle control.
• Assessment of DNA damage and cell death pathways (p53-p21).
• Identification of interacting proteins using biochemical and functional assays (PKNOX1).

Main Results:

• Yap knockdown accelerated S-phase and disrupted DNA replication, linked to c-Myc upregulation.
• Increased DNA damage and subsequent p53-p21 mediated cell death were observed after Yap knockdown.
• PKNOX1 was identified as a novel functional and physical interactor of YAP, involved in genomic stability.

Conclusions:

• YAP is essential for regulating DNA replication origin firing and quality control in adult retinal stem cells.
• Proper S-phase control mediated by YAP is critical for maintaining genomic stability in stem cells.
• These findings reveal a conserved mechanism for protecting stem cell integrity during proliferation.