Abstract
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.
Highlights
Astrocytes are multifunctional players in many aspects of brain physiology
Interleukin 6 (IL6)-related ligands such as cardiotrophin 1 (CT1)[9], leukemia inhibiting factor (LIF)[10], ciliary neurotrophic factor (CNTF)[11], neuropoietin (NP)[12] and cardiotrophin-like cytokine (CLC)[13] have been identified as astrogenic cytokines which bind to their corresponding receptor complexes to sequentially phosphorylate JAK and STAT3 leading to STAT3 homodimer formation
We show that constitutive Yes-associated protein (YAP) activation induces precocious glial fibrillary acidic protein (GFAP)+ cell production at late embryonic stages in a non-cell autonomous fashion using gain-of-function experiments based on retroviral transduction
Summary
Astrocytes are multifunctional players in many aspects of brain physiology. In addition to basic structural and metabolic support for neurons, astrocytes are known to regulate synaptic transmission[1], vasomodulation[2], formation and maintenance of the blood–brain barrier[3], and long-term potentiation[4]. Neural stem cells differentiate into neurons in mid-neurogenic stages, and into astrocytes around the birth date[8]. This temporal window of neurogenic-to-astrogenic transition was well recognized, the cell fate-regulatory mechanisms which trigger the intrinsic changes toward astrogenesis are still not fully understood. YAP was consistently identified as a positive regulator for neural stem cell pool expansion in the developing chick[21], frog[22] and mouse models[23] In this regard, it is of note that YAP was recently shown to be necessary for BMP2-induced astrogenesis in a conditional YAP knockout model[24,25]. Our study provides a potential mechanism by which a high level of YAP activation regulates astrocyte generation from progenitor cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
