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Lethal Phenotype-Based Database Screening Identifies Ceramide as a Negative Regulator of Primitive Streak Formation
Jing Pu1, Satoshi Kofuji1, Yoshimi Okamoto-Uchida1
1Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Abstract:
In early embryogenesis, the primitive streak (PrS) generates the mesendoderm and is essential for organogenesis. However, because the PrS is a minute and transient tissue, elucidating the mechanism of its formation has been challenging. We performed comprehensive screening of 2 knockout mouse databases based on the fact that failure of PrS formation is lethal. We identified 812 genes involved in various cellular functions and responses that might be linked to PrS formation, with the category of greatest abundance being "Metabolism." In this study, we focused on genes of sphingolipid metabolism and investigated their roles in PrS formation using an in vitro mouse ES cell differentiation system. We show here that elevated intracellular ceramide negatively regulates gene expression essential for PrS formation and instead induces neurogenesis. In addition, sphingosine-1-phosphate (a ceramide derivative) positively regulates neural maturation. Our results indicate that ceramide regulates both PrS formation and the induction of neural differentiation.
Insights
Sphingolipid metabolism, particularly ceramide, plays a crucial role in early embryogenesis. Elevated ceramide inhibits primitive streak formation and promotes neurogenesis, impacting organogenesis.
Area of Science:
- Developmental Biology
- Cellular Metabolism
- Molecular Genetics
Background:
- The primitive streak (PrS) is vital for mesendoderm generation and organogenesis during early embryogenesis.
- The PrS is a transient and small tissue, making its formation mechanisms difficult to study.
- Gene expression related to metabolism is abundant in genes influencing PrS formation.
Purpose of the Study:
- To investigate the role of sphingolipid metabolism genes in primitive streak formation.
- To elucidate the regulatory mechanisms of ceramide and its derivatives in early embryonic development.
Main Methods:
- Screening of knockout mouse databases to identify genes involved in PrS formation.
- Utilizing an in vitro mouse embryonic stem (ES) cell differentiation system.
- Analyzing the effects of altered ceramide and sphingosine-1-phosphate levels on gene expression and differentiation.
Main Results:
- Identified 812 genes linked to PrS formation, with metabolism-related genes being most abundant.
- Demonstrated that elevated intracellular ceramide inhibits gene expression critical for PrS formation.
- Showed that ceramide promotes neurogenesis, while sphingosine-1-phosphate enhances neural maturation.
Conclusions:
- Ceramide acts as a negative regulator of primitive streak formation.
- Ceramide and its derivatives are key regulators of both primitive streak formation and neural differentiation.
- Sphingolipid metabolism is a critical pathway influencing early embryonic developmental decisions.
