![]() Although previous studies have established that aberrant YAP/TAZ activation is detrimental to mammalian brain development, whether and how endogenous levels of YAP/TAZ activity regulate brain development remain unclear. ![]() It controls the activity of two paralogous transcriptional coactivators, YAP and TAZ (YAP/TAZ). The Hippo pathway regulates the development and homeostasis of many tissues and in many species. Our findings reveal a significant impact of YAP/TAZ activation on global transcription activity and have important implications for understanding YAP/TAZ function. Following a transient increase in proliferation, however, hypertranscription in neural progenitors triggers replication stress, DNA damage, and p53 activation, resulting in massive apoptosis. In contrast, conventional read-depth-normalized RNA-sequencing analysis failed to detect the scope of the transcriptome shift and missed most relevant gene ontologies. By analyzing the effects of inactivating LATS1/2 ki-nases, the direct upstream inhibitors of YAP/TAZ, on mouse brain development and applying cell-number-normalized transcriptome analyses, we discovered that YAP/TAZ activation causes a global increase in transcription activity, known as hypertranscrip-tion, and upregulates many genes associated with cell growth and proliferation. Despite the critical role of this pathway in tissue growth and tumorigenesis, it remains unclear how YAP/TAZ-mediated transcription drives proliferation. SUMMARY The Hippo pathway controls the activity of YAP/TAZ transcriptional coactivators through a kinase cascade. Hypertranscription in neural progenitors inhibits differentiation and triggers replication stress and DNA damage, resulting in massive apoptosis. show that inactivation of Hippo pathway LATS1/2 kinases during brain development causes YAP/TAZ-driven global hypertranscription, upregulating many genes involved in cell growth and proliferation. Graphical Abstract Highlights d Loss of Hippo pathway LATS kinase leads to YAP/TAZ-driven global hypertranscription d YAP/TAZ-driven hypertranscription upregulates many growth and proliferation genes d Hypertranscription impairs neural progenitor differentiation and causes apoptosis d Cell-number-normalized methods are required to detect global hypertranscription In Brief Using cell-number-normalized transcriptome analysis, Lavado et al.
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