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

Abstract

SUMMARY The Hippo pathway controls the activity of YAP/TAZ transcriptional coactivators through a kinase cascade. Despite the critical role of this pathway in tissue growth and tumorigenesis, it remains unclear how YAP/TAZ–mediated transcription drives proliferation. By analyzing the effects of inactivating LATS1/2 kinases, 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 hypertranscription, and upregulates many genes associated with cell growth and proliferation. In contrast, conventional read-depth–normalized RNA-sequencing analysis failed to detect the scope of the transcriptome shift and missed most relevant gene ontologies. Following a transient increase in proliferation, however, hypertranscription in neural progenitors triggers replication stress, DNA damage, and p53 activation, resulting in massive apoptosis. Our findings reveal a significant impact of YAP/TAZ activation on global transcription activity and have important implications for understanding YAP/TAZ function.

Homeostatic and tumourigenic activity of SOX2+ pituitary stem cells is controlled by the LATS/YAP/TAZ cascade

“…Deletion of Lats2 alone ( Hesx1 Cre/+ ;Lats2 fl/fl ), did not reveal any developmental morphological anomalies (SFig3D) and pups were identified at normal Mendelian proportions (Table 2). Similarly, deletion of any three out of four Lats alleles did not affect pituitary development and were identified at normal ratios, similar to other tissues 33 . Homozygous Hesx1 Cre/+ ;Lats1 fl/fl ;Lats2 fl/fl mutants were identified at embryonic stages at reduced Mendelian ratios and were absent at P0-P2, suggesting embryonic and perinatal lethality (Table 2).…”

TAZ functions as a tumor suppressor in multiple myeloma by downregulating MYC

“…24 Other studies show that uncontrolled YAP and TAZ activity after genetic deletion of LATS1/2 inhibits colon cancer cell growth particularly in cell-suspension conditions 49 or leads to hypertranscription and massive cell death in cells that are particularly sensitive to DNA damage. 50 This cell death occurs through the selective regulation of Figure 6. (continued) increasing concentration of DAC for 48 hours followed by exposure to TSA for 72 hours before cell viability was assessed and CI values calculated.…”

A SMAD1/5-YAP signaling module drives radial glia self-amplification and growth of the developing cerebral cortex

“…Accordingly, the tight regulation of YAP activity appears to be crucial for correct brain formation and growth. Cortical and general brain development is affected when YAP activity is enhanced, either directly or indirectly (Lavado et al, 2013;Lavado et al, 2018;Liu et al, 2018;Saito et al, 2018). More importantly, an aberrant increase in YAP activity has been linked to various types of cortical heterotopia, such as those observed in the Van Maldergem syndrome (Cappello et al, 2013;Liu et al, 2018).…”