Non-cell autonomous promotion of astrogenesis at late embryonic stages by constitutive YAP activation

Although astrocytes have gained increased recognition as an important regulator in normal brain function and pathology, the mechanisms underlying their genesis are not well understood. In this study, we show that constitutive YAP activation by in utero introduction of a non-degradable form of the YAP gene (YAP 5SA) causes productive GFAP(+) cell generation at late embryonic periods, and this activity is nuclear localization- and TEAD transcription factor-dependent. Moreover, we found that the GFAP(+) cells were not YAP 5SA-expressing cells themselves but cells in the vicinity in vivo. Conditioned medium prepared from YAP 5SA-expressing cells induced GFAP(+) cell production in vitro, suggesting that a soluble factor(s) was mediating the astrogenic activity of YAP 5SA. Indeed, YAP 5SA expression greatly increased CNTF and BMP4 transcription in neural progenitor cells, and a neutralizing antibody against CNTF reduced the astrogenic effects of YAP 5SA-conditioned medium. Furthermore, the YAP 5SA-expressing cells were identified as FN1(+) mesenchymal cells which are responsible for the precocious astrogenesis. These results suggest a novel molecular mechanism by which YAP activation can induce astrogenesis in a non-cell autonomous manner.