The Hippo Pathway Prevents YAP/TAZ-Driven Hypertranscription and Controls Neural Progenitor Number

Area of Science:

• Cell Biology
• Developmental Biology
• Genetics

Background:

• The Hippo pathway regulates YAP/TAZ transcriptional coactivators, crucial for tissue growth and cancer.
• The precise mechanisms by which YAP/TAZ drives proliferation remain incompletely understood.

Purpose of the Study:

• To investigate the transcriptional consequences of YAP/TAZ activation during mouse brain development.
• To elucidate the role of YAP/TAZ in regulating cell proliferation and its downstream effects.

Main Methods:

• Inactivation of LATS1/2 kinases, upstream inhibitors of YAP/TAZ, in mouse brain development.
• Cell-number-normalized transcriptome analyses to assess global transcription changes.
• Comparison with conventional RNA-sequencing methods.

Main Results:

• YAP/TAZ activation induces hypertranscription, a global increase in transcription activity.
• Upregulation of numerous genes involved in cell growth and proliferation was observed.
• Hypertranscription in neural progenitors triggered replication stress, DNA damage, and p53 activation, leading to apoptosis.

Conclusions:

• YAP/TAZ activation has a profound impact on global transcription, termed hypertranscription.
• While initially promoting proliferation, sustained hypertranscription leads to cell death via DNA damage.
• Findings offer critical insights into YAP/TAZ function in development and disease.