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Neural crest cells (NCCs) are multipotent stem cells that can differentiate into multiple cell types, including the osteoblasts and chondrocytes, and constitute most of the craniofacial skeleton. Here, we show through in vitro and in vivo studies that the transcriptional regulators Yap and Taz have redundant functions as key determinants of the specification and differentiation of NCCs into osteoblasts or chondrocytes. Primary and cultured NCCs deficient in Yap and Taz switched from osteogenesis to chondrogenesis, and NCC-specific deficiency for Yap and Taz resulted in bone loss and ectopic cartilage in mice. Yap bound to the regulatory elements of key genes that govern osteogenesis and chondrogenesis in NCCs and directly regulated the expression of these genes, some of which also contained binding sites for the TCF/LEF transcription factors that interact with the Wnt effector β-catenin. During differentiation of NCCs in vitro and NCC-derived osteogenesis in vivo, Yap and Taz promoted the expression of osteogenic genes such as Runx2 and Sp7 but repressed the expression of chondrogenic genes such as Sox9 and Col2a1. Furthermore, Yap and Taz interacted with β-catenin in NCCs to coordinately promote osteoblast differentiation and repress chondrogenesis. Together, our data indicate that Yap and Taz promote osteogenesis in NCCs and prevent chondrogenesis, partly through interactions with the Wnt–β-catenin pathway. Switching from chondrogenesis to osteogenesis with Yap/Taz: The transcriptional regulators Yap and Taz play important roles in the specification and differentiation of mesenchymal stem cells into the osteoblasts and chondrocytes that build the skeleton of the trunk and limbs. Through experiments in vitro and in mice, Zhao et al. found that they were also required for the proper specification and differentiation of cranial neural crest cells (NCCs) into the osteoblasts and chondrocytes that give rise to the bones and cartilage of the face and skull. Yap and Taz were required for the differentiation of NCCs into bipotent osteochondral progenitors and, subsequently, osteoblasts. In osteochondral progenitors, Yap and Taz promoted the expression of osteogenic genes and repressed the expression of chondrogenic genes, likely in cooperation with the Wnt signaling effector β-catenin. Thus, Yap and Taz promote osteogenic lineage commitment in NCCs by both promoting one cell fate and repressing another. [ABSTRACT FROM AUTHOR]

RIP1 has emerged as a master regulator in TNFα signaling that controls two distinct cellular fates: cell survival versus programmed cell death. Because the default response of most cells to TNFα is NF-κB–mediated inflammation and survival, a specific mechanism must exist to control the divergence of signaling outcome. Here, we identify HSPA13 as a transcription-independent checkpoint to modulate the role of RIP1 in TNFα signaling. Through specific binding to TNFR1 and RIP1, HSPA13 enhances TNFα-induced recruitment of RIP1 to TNFR1, and consequently promotes downstream NF-κB transcriptional responses. Meanwhile, HSPA13 attenuates the participation of RIP1 in cytosolic complex II and prevents cells from programmed death. Loss of HSPA13 shifts the transition of RIP1 from complex I to complex II and promotes both apoptosis and necroptosis. Thus, our study provides compelling evidence for the cellular protective function of HSPA13 in fine-tuning TNFα responses.