SIRT1 regulates sphingolipid metabolism and neural differentiation of mouse embryonic stem cells through c-Myc-SMPDL3B
0301 basic medicine
Transcription, Genetic
QH301-705.5
Science
Neurogenesis
sphingomyelin degradation
neural development
Cell Line
Proto-Oncogene Proteins c-myc
Mice
03 medical and health sciences
SIRT1
Neural Stem Cells
Sirtuin 1
Animals
Biology (General)
Mice, Knockout
Sphingolipids
0303 health sciences
Q
R
Gene Expression Regulation, Developmental
Mouse Embryonic Stem Cells
Cell Biology
embryonic stem cells
Cyclic Nucleotide Phosphodiesterases, Type 3
3. Good health
Mice, Inbred C57BL
c-Myc
Medicine
embryogenesis
Signal Transduction
DOI:
10.7554/elife.67452
Publication Date:
2021-05-27T12:00:40Z
AUTHORS (10)
ABSTRACT
Sphingolipids are important structural components of cell membranes and prominent signaling molecules controlling cell growth, differentiation, and apoptosis. Sphingolipids are particularly abundant in the brain, and defects in sphingolipid degradation are associated with several human neurodegenerative diseases. However, molecular mechanisms governing sphingolipid metabolism remain unclear. Here, we report that sphingolipid degradation is under transcriptional control of SIRT1, a highly conserved mammalian NAD+-dependent protein deacetylase, in mouse embryonic stem cells (mESCs). Deletion of SIRT1 results in accumulation of sphingomyelin in mESCs, primarily due to reduction of SMPDL3B, a GPI-anchored plasma membrane bound sphingomyelin phosphodiesterase. Mechanistically, SIRT1 regulates transcription of Smpdl3b through c-Myc. Functionally, SIRT1 deficiency-induced accumulation of sphingomyelin increases membrane fluidity and impairs neural differentiation in vitro and in vivo. Our findings discover a key regulatory mechanism for sphingolipid homeostasis and neural differentiation, further imply that pharmacological manipulation of SIRT1-mediated sphingomyelin degradation might be beneficial for treatment of human neurological diseases.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (64)
CITATIONS (29)
EXTERNAL LINKS
PlumX Metrics
RECOMMENDATIONS
FAIR ASSESSMENT
Coming soon ....
JUPYTER LAB
Coming soon ....