Two distinct modes of Vgll4-mediated Tead regulation control organ size in zebrafish - SourceData

Control of organ size during development and homeostasis relies on balanced regulation of Hippo pathway transcriptional output, yet how TEAD activity is precisely regulated in vivo remains unclear. Using the zebrafish posterior lateral line (pLL) we show that Yap1 is required early in pLL progenitors to ensure sufficient cell numbers in the migrating primordium. In contrast, the two zebrafish Vgll4 paralogs, Vgll4b and Vgll4l, act partially redundantly to limit pLLP size and cell number. Through loss- and gain-of-function analyses, epistasis experiments, transcriptional reporter quantification and pharmacological treatments, we find that Vgll4 restricts Tead-dependent transcription through two co-existing mechanisms: inhibition of Yap1–Tead–mediated transcriptional activation and Tead-dependent repression. Together, our findings reconcile the competitive and default repression models of VGLL4 function and provide an integrated framework for how VGLL4 fine-tunes TEAD output to control tissue growth in vivo.