Llgl1 Connects Cell Polarity with Cell-Cell Adhesion in Embryonic Neural Stem Cells

Area of Science:

• Neuroscience
• Developmental Biology
• Cell Biology

Background:

• Malformations of the cerebral cortex (MCCs) are severe developmental disorders.
• Cell polarity proteins are crucial for forming apical junctional complexes (AJCs), but the precise mechanisms are not fully understood.

Purpose of the Study:

• To investigate the role of LLGL1, a mammalian cell polarity gene, in mammalian brain development.
• To elucidate the molecular mechanisms by which LLGL1 regulates cell adhesion and prevents MCCs.

Main Methods:

• Generated mice with embryonic neural stem-cell-specific deletion of Llgl1 (Nestin-Cre/Llgl1^fl/fl).
• Utilized immunohistochemical analyses and live cortical imaging to study periventricular heterotopia (PH) formation.
• Investigated the interaction between LLGL1 and N-cadherin, and the effect of protein kinase C phosphorylation.

Main Results:

• Llgl1 deletion in neural stem cells led to MCCs resembling severe periventricular heterotopia (PH).
• Disruption of AJCs was identified as the cause of PH in the mutant brains.
• LLGL1 directly binds to and promotes N-cadherin internalization, an interaction regulated by atypical protein kinase C phosphorylation.

Conclusions:

• LLGL1 plays a critical role in maintaining cerebral cortex development by regulating cell-cell adhesion through N-cadherin.
• The N-cadherin-LLGL1 interaction, modulated by phosphorylation, is essential for restricting AJC accumulation and preventing PH.
• This study reveals a key mechanism connecting cell polarity and cell-cell adhesion in mammalian development.