The GTPase Rab21 is required for neuronal development and migration in the cerebral cortex

PERALTA CUASOLO, YAEL MACARENA; DUPRAZ, SEBASTIÁN; UNSAIN, NICOLAS; BISBAL, MARIANO; QUASSOLLO, GONZALO; GALIANO, MAURICIO R.; GRASSI, DIEGO; QUIROGA, SANTIAGO; SOSA, LUCAS JAVIER

JOURNAL OF NEUROCHEMISTRY

WILEY-BLACKWELL PUBLISHING, INC

Año: 2023

0022-3042

Development of the mammalian neocortex requires proper inside-out migration ofdeveloping cortical neurons from the germinal ventricular zone toward the corticalplate. The mechanics of this migration requires precise coordination of different cel-lular phenomena including cytoskeleton dynamics, membrane trafficking, and cell ad-hesion. The small GTPases play a central role in all these events. The small GTPaseRab21 regulates migration and neurite growth in developing neurons. Moreover, reg-ulators and effectors of Rab21 have been implicated in brain pathologies with corticalmalformations, suggesting a key function for the Rab21 signaling pathway in corticaldevelopment. Mechanistically, it has been posited that Rab21 influences cell migra-tion by controlling the trafficking of endocytic vesicles containing adhesion molecules.However, direct evidence of the participation of Rab21 or its mechanism of action inthe regulation of cortical migration is still incomplete. In this study, we demonstratethat Rab21 plays a critical role in the differentiation and migration of pyramidal neu-rons by regulating the levels of the amyloid precursor protein on the neuronal cell sur-face. Rab21 loss of function increased the levels of membrane-exposed APP, resultingin impaired cortical neuronal differentiation and migration. These findings further ourunderstanding of the processes governing the development of the cerebral cortexand shed light onto the molecular mechanisms behind cortical development disordersderived from the malfunctioning of Rab21 signaling effectors.