TY - JOUR
T1 - Atypical protein kinase C iota (PKC?/?) ensures mammalian development by establishing the maternal-fetal exchange interface
AU - Bhattacharya, Bhaswati
AU - Home, Pratik
AU - Home, Pratik
AU - Ganguly, Avishek
AU - Ray, Soma
AU - Ghosh, Ananya
AU - Islam, Md Rashedul
AU - French, Valerie
AU - French, Valerie
AU - Marsh, Courtney
AU - Marsh, Courtney
AU - Gunewardena, Sumedha
AU - Okae, Hiroaki
AU - Arima, Takahiro
AU - Paul, Soumen
AU - Paul, Soumen
AU - Paul, Soumen
N1 - Funding Information:
ACKNOWLEDGMENTS. This research was supported by NIH Grants HD062546, HD101319, HD0098880, and HD079363; bridging grant support under the Kansas Idea Network of Biomedical Research Excellence (P20GM103418) to S.P.; a University of Kansas Biomedical Research Training Program grant to B.B.; and a NIH Center of Biomedical Research Program (P30GM122731) pilot grant to P.H. This study was supported by various core facilities, including the Genomics Core, Transgenic and Gene Targeting Institutional Facility, Imaging and Histology Core Facility, and the Bioinformatics Core of the University of Kansas Medical Center.
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/6/23
Y1 - 2020/6/23
N2 - In utero mammalian development relies on the establishment of the maternal-fetal exchange interface, which ensures transportation of nutrients and gases between the mother and the fetus. This exchange interface is established via development of multinucleated syncytiotrophoblast cells (SynTs) during placentation. In mice, SynTs develop via differentiation of the trophoblast stem cell-like progenitor cells (TSPCs) of the placenta primordium, and in humans, SynTs are developed via differentiation of villous cytotrophoblast (CTB) progenitors. Despite the critical need in pregnancy progression, conserved signaling mechanisms that ensure SynT development are poorly understood. Herein, we show that atypical protein kinase C iota (PKCγ/ι) plays an essential role in establishing the SynT differentiation program in trophoblast progenitors. Loss of PKCγ/ι in the mouse TSPCs abrogates SynT development, leading to embryonic death at approximately embryonic day 9.0 (E9.0).We also show that PKCγ/ι-mediated priming of trophoblast progenitors for SynT differentiation is a conserved event during human placentation. PKCγ/ι is selectively expressed in the first-trimester CTBs of a developing human placenta. Furthermore, loss of PKCγ/ι in CTB-derived human trophoblast stem cells (human TSCs) impairs their SynT differentiation potential both in vitro and after transplantation in immunocompromised mice. Our mechanistic analyses indicate that PKCγ/ι signaling maintains expression of GCM1, GATA2, and PPARγ, which are key transcription factors to instigate SynT differentiation programs in both mouse and human trophoblast progenitors. Our study uncovers a conserved molecular mechanism, in which PKCγ/ι signaling regulates establishment of the maternal-fetal exchange surface by promoting trophoblast progenitor-to-SynT transition during placentation.
AB - In utero mammalian development relies on the establishment of the maternal-fetal exchange interface, which ensures transportation of nutrients and gases between the mother and the fetus. This exchange interface is established via development of multinucleated syncytiotrophoblast cells (SynTs) during placentation. In mice, SynTs develop via differentiation of the trophoblast stem cell-like progenitor cells (TSPCs) of the placenta primordium, and in humans, SynTs are developed via differentiation of villous cytotrophoblast (CTB) progenitors. Despite the critical need in pregnancy progression, conserved signaling mechanisms that ensure SynT development are poorly understood. Herein, we show that atypical protein kinase C iota (PKCγ/ι) plays an essential role in establishing the SynT differentiation program in trophoblast progenitors. Loss of PKCγ/ι in the mouse TSPCs abrogates SynT development, leading to embryonic death at approximately embryonic day 9.0 (E9.0).We also show that PKCγ/ι-mediated priming of trophoblast progenitors for SynT differentiation is a conserved event during human placentation. PKCγ/ι is selectively expressed in the first-trimester CTBs of a developing human placenta. Furthermore, loss of PKCγ/ι in CTB-derived human trophoblast stem cells (human TSCs) impairs their SynT differentiation potential both in vitro and after transplantation in immunocompromised mice. Our mechanistic analyses indicate that PKCγ/ι signaling maintains expression of GCM1, GATA2, and PPARγ, which are key transcription factors to instigate SynT differentiation programs in both mouse and human trophoblast progenitors. Our study uncovers a conserved molecular mechanism, in which PKCγ/ι signaling regulates establishment of the maternal-fetal exchange surface by promoting trophoblast progenitor-to-SynT transition during placentation.
KW - Cytotrophoblast
KW - Human trophoblast stem cell
KW - Placenta
KW - Protein kinase Cγ/ι
KW - Syncytiotrophoblast
UR - http://www.scopus.com/inward/record.url?scp=85087096691&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85087096691&partnerID=8YFLogxK
U2 - 10.1073/pnas.1920201117
DO - 10.1073/pnas.1920201117
M3 - Article
C2 - 32513715
AN - SCOPUS:85087096691
VL - 117
SP - 14280
EP - 14291
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 25
ER -