Abstract :
[en] Cortical interneuron migration is a critical step in human brain development, and its
disruption contributes to a spectrum of neurodevelopmental disorders, including cortical
malformations. While much attention has been paid to excitatory projection neurons, the
role of inhibitory interneurons in cortical malformation syndromes remains underexplored.
In this study, we investigated the function of Neural precursor cell expressed
developmentally downregulated gene 4-like (NEDD4-2), an E3 ubiquitin ligase mutated in
Periventricular Nodular Heterotopia type 7, focusing on its role in cIN migration during
embryogenesis. Using a conditional knockout mouse model, we demonstrate that NEDD4-2
is essential for multiple stages of cortical interneuron migration, including process
branching, swelling formation, and somal translocation. Mechanistically, branching defects
were linked to disrupted microtubule dynamics, while nuclear translocation impairments
were associated with altered actomyosin contractility. We identified Actin Related Protein
2/3 Complex Subunit 1A (ARPC1A) and Valosin-Containing Protein (VCP) as putative NEDD4-
2 substrates contributing to these phenotypes. To assess the pathogenicity of patient-
derived mutations, we employed two complementary systems: a conditional knock-in mouse
expressing a Periventricular Nodular Heterotopia type 7-associated mutation, and ventral
forebrain organoids derived from induced pluripotent stem cells of two affected individuals.
Both models recapitulated key aspects of the migration phenotype seen in the knockout,
albeit with variable severity and mechanistic nuance, highlighting the importance of
developmental context and interspecies differences. Altogether, this work establishes
NEDD4-2 as a crucial regulator of cIN migration and implicates its dysfunction in the
pathogenesis of Periventricular Nodular Heterotopia type 7. Our findings underscore the
value of integrative, multi-model approaches to dissect the cellular basis of cortical
malformations and identify potential molecular targets for future therapeutic intervention.
