SARA involvement in modulating TGFβ signaling during neural development

CHRISTIAN GONZALEZ BILLAULT; CARLOS WILSON; VICTORIA ROZÉS SALVADOR; CECILIA CONDE

Cordoba

Congreso; Congreso Anual Sociedad Argentina de Neurociencia; 2019

Sociedad Argentina de Neurociencias

Several events are necessary for proper neuronal development, such as cytoskeleton dynamics and endosome trafficking. SARA is a protein that binds to early endosomes; performing both traffic and signaling functions, as in the transforming growth factor β (TGFβ) pathway. In this sense, it has been described that SARA recruits Smad2/3, favoring the activation of this pathway; but it can also modulate the inactivation of TβRI by PP1c in both epithelial cells and cell lines. In addition, TGFβ signaling has been shown to specify the axon during neuronal development; however, the participation of SARA in this signaling pathway during development remains unknown. For this reason, we proposed to analyze the role of SARA in TGFβ signaling during neuronal development. Results obtained in cultures of hippocampal neurons, by FRET showed physical interaction between SARA and TβRI. In addition, performing experiments of loss and gain of function, we found that dominant-negative form of SARA (SARA-F728A) generates greater axonal growth and loss of axonal specification compared to control condition. Interestingly, this mutant alters its binding to the PP1c protein, keeping the TGFβ pathway over-activated. Also by FRET, we find that SARA-F728A has more interaction with PP1c and GADD34 than control, suggesting that SARA prevents TβRI dephosphorylation. These results suggest that SARA negatively modulates the TGFβ pathway, which seems to be a necessary requirement for proper axon specification.