PCSK9 Loss-of-Function Disrupts Cellular Microfilament Network via LIN28A/HES5/JMY Axis in Neural Tube Defects

Area of Science:

• Developmental Biology
• Neuroscience
• Genetics

Background:

• Neural tube defects (NTDs) are severe congenital malformations affecting the central nervous system.
• PCSK9 is a known prenatal diagnostic marker for NTDs, but its pathogenic role is unknown.

Purpose of the Study:

• To elucidate the role of PCSK9 in neural tube development and NTD pathogenesis.
• To identify the molecular mechanisms by which PCSK9 influences neurulation.

Main Methods:

• Utilized PCSK9 knockout embryonic stem cells (ESCs) in neural organoid (NO) and neural progenitor cell (NPC) models.
• Performed transcriptome sequencing and zebrafish model experiments.
• Investigated the interaction between PCSK9, LIN28A, HES5, and JMY.

Main Results:

• PCSK9 loss resulted in incomplete neural tube structures in NOs and microfilament disorder in NPCs.
• PCSK9 deficiency led to NTDs via the JMY molecule, confirmed by zebrafish studies.
• PCSK9 acts as a molecular chaperone, promoting LIN28A degradation, which affects JMY expression through HES5.

Conclusions:

• PCSK9 loss disrupts the cellular microfilament network through the LIN28A/HES5/JMY pathway, causing NTDs.
• These findings provide crucial insights into NTD pathogenesis and potential therapeutic strategies.