The physiological role of the GTPase Rab21 in neuronal migration and the development of Down syndrome cerebral cortex.

MAYRA PEROTTI; SEBASTIAN DUPRAZ; SANTIAGO QUIROGA; LUCAS J. SOSA

BARCELONA

Congreso; 3rd International Conference Trisomy 21 Research Society; 2019

Trisomy 21 Research Society

Down syndrome (DS) patients present atypical brain development caused by still undefined cellular and molecular mechanisms. Normal cerebral cortex requires the proper migration of developing neurons from the ventricular zone to the cortical plate. The precise coordination of different cellular processes such as cytoskeleton dynamics, membrane trafficking, and cell adhesion during migration and axonal pathfinding is achieved by a variety of signaling pathways. GTPases play a central role in all these processes. In this regard, the small GTPase Rab21 is a misexpressed gene in DS as a result of genome-wide dosage effects. Rab21 is implicated in the processing of amyloid precursor protein (APP), amyloid beta generation and regulation of cell adhesion dynamics. APP itself is overexpressed in DS, leading up to aberrant cell adhesion and growth cone contact guidance.Within this perspective, these results are aimed to elucidate whether Rab21 regulates the trafficking and insertion of APP into the neuronal cell membrane and its implications for both neuronal migration and axonal path-finding in the developmental Down syndrome cerebral cortex. In order to address these issues, we are using a variety of techniques, including biochemistry, in utero electroporation (IUE), cell culture, Down syndrome mice models and cell lines and advanced light microscopy.We expressed dominant negative Rab21 (T31N) in the embryonic cortex by in utero electroporation. In contrast to controls, neurons expressing Rab21 (T31N) were arrested within the VZ/SVZ, suggesting the involvement of Rab21 in neuronal migration. Notably, the neurons that fail to enter the cortical plate showed increased neurite branching and multipolar morphology.These results will help to understand potential links of the Rab21 signaling pathway to APP regulation and function in Down syndrome cortex organization, might shed light onto cognitive deficits in Down syndrome, and ultimately contribute to the foundation of novel therapeutic interventions.