Impaired yolk sac NAD metabolism disrupts murine embryogenesis with relevance to human birth defects

Area of Science:

• Developmental Biology
• Metabolic Pathways
• Human Genetics

Background:

• Congenital malformations often have unknown causes, but genetic disruption of nicotinamide adenine dinucleotide (NAD) de novo synthesis leads to Congenital NAD Deficiency Disorder (CNDD).
• NAD synthesis is vital for embryogenesis, but its location during early development, prior to the liver's postnatal dominance, remains unclear.
• Previous research indicates NAD deficiency specifically impacts organogenesis in mouse embryos.

Purpose of the Study:

• To investigate the site of NAD de novo synthesis during early embryogenesis in a mouse model of human CNDD.
• To determine the role of extraembryonic tissues in NAD production during organogenesis.
• To elucidate the impact of impaired NAD synthesis on embryonic development and metabolism.

Main Methods:

• Utilized a mouse model mimicking human CNDD.
• Analyzed gene expression, enzyme activity, and metabolic profiles in embryonic livers and extraembryonic tissues.
• Assessed NAD synthesis functionality in the visceral yolk sac endoderm.

Main Results:

• The visceral yolk sac endoderm exclusively synthesizes NAD de novo during early organogenesis, preceding the embryonic liver's function.
• CNDD conditions resulted in reduced NAD levels and altered metabolic profiles in visceral yolk sacs, impacting embryo metabolism.
• Genes involved in NAD synthesis are conserved in the human yolk sac equivalent.

Conclusions:

• Visceral yolk sac-mediated NAD de novo synthesis is essential for mouse embryogenesis.
• Perturbation of this pathway causes CNDD, with implications for understanding human congenital malformations.
• Functional homology between mouse and human yolk sacs suggests these findings are relevant to human development.