Neural tube closure requires the endocytic receptor Lrp2 and its functional interaction with intracellular scaffolds

Area of Science:

• Developmental Biology
• Genetics
• Cell Biology

Background:

• Pathogenic mutations in the LRP2 gene are linked to severe neural tube defects (NTDs) in humans, including anencephaly and spina bifida.
• Understanding the precise mechanisms underlying LRP2-related NTDs is crucial for potential therapeutic interventions.

Purpose of the Study:

• To investigate the role of LRP2 in neural tube closure using mouse and Xenopus laevis models.
• To elucidate the molecular etiology of LRP2-associated NTDs and identify interacting proteins.

Main Methods:

• Comparative analysis of neural tube closure in Lrp2 loss-of-function mouse and Xenopus laevis models.
• Assessment of neuroepithelial morphogenesis, apical constriction, and planar cell polarity (PCP) protein localization.
• Identification of novel protein interactions using molecular biology techniques.

Main Results:

• Loss of Lrp2 function impaired neuroepithelial morphogenesis and neural tube closure in both model organisms.
• Lrp2 deficiency disrupted apical constriction and Vangl2 localization, indicating a conserved role in neural tube formation.
• A novel functional interaction between LRP2, Shroom3, and Gipc1 in the developing forebrain was identified.

Conclusions:

• LRP2 plays a conserved, essential role in regulating apical constriction and PCP component trafficking during neurulation.
• Motifs within LRP2's intracellular domain orchestrate endocytic membrane removal and protein trafficking for efficient neural tube development.
• This study provides new insights into the etiology of LRP2-related NTDs and highlights LRP2 as a key regulator of fundamental developmental processes.