Abstract
ABSTRACTThe Hippo-YAP/TAZ pathway is an important regulator of tissue growth, but can also control cell fate or tissue morphogenesis. Here, we investigate the function of the Hippo pathway during the development of cartilage, which forms the majority of the skeleton. Previously, YAP was proposed to inhibit skeletal size by repressing chondrocyte proliferation and differentiation. We find that, in vitro, Yap/Taz double knockout impairs murine chondrocyte proliferation, whereas constitutively nuclear nls-YAP5SA accelerates proliferation, in line with the canonical role of this pathway in most tissues. However, in vivo, cartilage-specific knockout of Yap/Taz does not prevent chondrocyte proliferation, differentiation or skeletal growth, but rather results in various skeletal deformities including cleft palate. Cartilage-specific expression of nls-YAP5SA or knockout of Lats1/2 do not increase cartilage growth, but instead lead to catastrophic malformations resembling chondrodysplasia or achondrogenesis. Physiological YAP target genes in cartilage include Ctgf, Cyr61 and several matrix remodelling enzymes. Thus, YAP/TAZ activity controls chondrocyte proliferation in vitro, possibly reflecting a regenerative response, but is dispensable for chondrocyte proliferation in vivo, and instead functions to control cartilage morphogenesis via regulation of the extracellular matrix.
Highlights
The Hippo signalling pathway was discovered as a potent regulator of organ size in Drosophila, and is conserved in mammals (Harvey and Tapon, 2007; Moya and Halder, 2019; Pan, 2007; Yu et al, 2015; Zheng and Pan, 2019)
Control chondrocytes plated at low density (3000 cells/well of a 96-well plate) flattened and proliferated, Yapfl/flTazfl/flCol2a1cre+ve chondrocytes at the same density exhibited an almost a complete arrest in proliferation and maintained a strikingly rounder morphology, consistent with the known roles of YAP/TAZ in regulating integrin adhesion in cell culture (Nardone et al, 2017) or an indication of a difference in rate of differentiation (Fig. 1A,B; Fig. S1A,B,F)
YAP/TAZ are not required for cell proliferation in the cartilage growth plate in vivo To investigate the cellular basis for the YAP/TAZ loss-of-function phenotype in cartilage, we focused on the growth plate of the proximal tibia, a commonly examined cartilage structure for the study of chondrocyte proliferation and differentiation in vivo
Summary
The Hippo signalling pathway was discovered as a potent regulator of organ size in Drosophila, and is conserved in mammals (Harvey and Tapon, 2007; Moya and Halder, 2019; Pan, 2007; Yu et al, 2015; Zheng and Pan, 2019) This tumour suppressor pathway consists of a core kinase cascade in which the upstream kinase MST1/2 (Hippo in Drosophila) phosphorylates the downstream kinase LATS1/2 (Warts in Drosophila), which in turn phosphorylates and inactivates the pro-proliferative transcriptional co-activators YAP (Yes-associated protein, known as YAP1) and TAZ The Hippo-YAP/TAZ pathway can have a third and distinct function in regulating morphogenesis and organ shape during development of some mammalian tissues, such as kidney (Reginensi et al, 2016, 2015, 2013) and blood vessels (Kim et al, 2017; Neto et al, 2018; Wang et al, 2017)
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