TY - JOUR
T1 - Noncanonical Notch signals have opposing roles during cardiac development
AU - Miyamoto, Matthew
AU - Andersen, Peter
AU - Sulistio, Edrick
AU - Liu, Xihe
AU - Murphy, Sean
AU - Kannan, Suraj
AU - Nam, Lucy
AU - Miyamoto, William
AU - Tampakakis, Emmanouil
AU - Hibino, Narutoshi
AU - Uosaki, Hideki
AU - Kwon, Chulan
N1 - Publisher Copyright:
© 2021 The Authors
PY - 2021/11/5
Y1 - 2021/11/5
N2 - The Notch pathway is an ancient intercellular signaling system with crucial roles in numerous cell-fate decision processes across species. While the canonical pathway is activated by ligand-induced cleavage and nuclear localization of membrane-bound Notch, Notch can also exert its activity in a ligand/transcription-independent fashion, which is conserved in Drosophila, Xenopus, and mammals. However, the noncanonical role remains poorly understood in in vivo processes. Here we show that increased levels of the Notch intracellular domain (NICD) in the early mesoderm inhibit heart development, potentially through impaired induction of the second heart field (SHF), independently of the transcriptional effector RBP-J. Similarly, inhibiting Notch cleavage, shown to increase noncanonical Notch activity, suppressed SHF induction in embryonic stem cell (ESC)-derived mesodermal cells. In contrast, NICD overexpression in late cardiac progenitor cells lacking RBP-J resulted in an increase in heart size. Our study suggests that noncanonical Notch signaling has stage-specific roles during cardiac development.
AB - The Notch pathway is an ancient intercellular signaling system with crucial roles in numerous cell-fate decision processes across species. While the canonical pathway is activated by ligand-induced cleavage and nuclear localization of membrane-bound Notch, Notch can also exert its activity in a ligand/transcription-independent fashion, which is conserved in Drosophila, Xenopus, and mammals. However, the noncanonical role remains poorly understood in in vivo processes. Here we show that increased levels of the Notch intracellular domain (NICD) in the early mesoderm inhibit heart development, potentially through impaired induction of the second heart field (SHF), independently of the transcriptional effector RBP-J. Similarly, inhibiting Notch cleavage, shown to increase noncanonical Notch activity, suppressed SHF induction in embryonic stem cell (ESC)-derived mesodermal cells. In contrast, NICD overexpression in late cardiac progenitor cells lacking RBP-J resulted in an increase in heart size. Our study suggests that noncanonical Notch signaling has stage-specific roles during cardiac development.
KW - Heart development
KW - Noncanonical Notch signaling
KW - Notch signaling
KW - Second heart field
UR - http://www.scopus.com/inward/record.url?scp=85114171558&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85114171558&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2021.08.094
DO - 10.1016/j.bbrc.2021.08.094
M3 - Article
C2 - 34487959
AN - SCOPUS:85114171558
SN - 0006-291X
VL - 577
SP - 12
EP - 16
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
ER -