Deciphering the regulatory pathways in skeletal muscle lineage organized by the YAP1/TAZ-TEAD transcriptional network

Abstract

Recently, we reported that YAP1/TAZ-TEAD1/TEAD4 signaling regulates synaptic gene expression and acetylcholine receptor clustering at neuromuscular junctions (NMJs). Here, we looked for further impairments in skeletal muscle of Yap1 and/or Wwtr1 (protein called TAZ) conditional knockout mice. Single knockout muscles have an increased number of central nuclei and Wwtr1-deficient muscles possess more type I and less type IIa fibers. Fiber cross sectional areas were larger in Wwtr1-deficient muscles. However, adult Yap1-, but not Wwtr1-, deficient muscles showed reduced transcript levels of Axin2; Ctnnb1 was lower in both mutants. Both adult single knockout muscles transcribed less Myod and Myog. It was reported that double knockout mice do not survive past birth, likely due to the absence of NMJs. On further inspection, double knockout neonates had severely reduced muscle diameters, consistent with the impaired myogenic proliferation and sarcomere disorganization. Transcriptomic analysis demonstrates severely impaired myogenic transcription of several sarcomere genes in double knockout muscles; particularly Myh genes. Comparisons with available ChIP-seq data identified myogenic targets of YAP1/TAZ-TEAD signaling. ChIP-seq fragments of representative targets, like Myh3, Myl1, Myl2, and Ttn, overlapped with evolutionarily conserved regions and possess M-CAT motifs. Our data identified a role for YAP1/TAZ-TEAD signaling in muscle development and sarcomere structure.