Biological effects of GDNF/GFRα1 on neural cortical progenitors

BONAFINA, A; FONTANET, P; ALSINA, F; IRALA, D; PARATCHA, G; LEDDA, F

Rosario

Congreso; L Congreso Anual de la Sociedad Argentina de Bioquimica y Biología Molecular; 2014

SOciedad Argentina de Investigacion Bioquímica y Biología Molecular

The generation of differentiatied neurons from proliferating mammalian progenitor cells is a complex process involving an interplay between intrinsic cellular programs and extrinsic cues such as growth factors. In rodents, progenitor cells proliferate in the cortical ventricular zone and then differentiate into neurons and glial cells. One of these factors that might play a role in regulate cortical progenitor cell biology are the member of the GDNF derived family ligands. Reverse transcription analysis of total RNA isolated from forebrain precursors shows that GDNF receptor, GFRα1, is expressed at early developmental stages in the forebrain suggesting that GDNF/GFRα1 might play a role in cortical precursor development. Here we show that cultured cortical progenitors maintained in proliferating conditions shows lower levels of GFRα1 expression than precursors maintained in differentiating conditions. Furthermore, precursors growth in presence of GDNF results in a significant increase in neurite branch complexity and length of the differentiated post mitotic neurons. Notably, the percentage of Ki67 positive proliferative progenitors decreased significantly upon GDNF treatment. Addition of GDNF to proliferating progenitors forming neuroespheres resulted in the downregulation of cyclin D and E, which are necessary for cell cycle progression, and in the upregulation of p21, a potent cyclin-dependent kinase inhibitor, showing that GDNF induces an arrest of cell cycle of cortical precursors. Thus, our results indicate that GDNF/GFRα1 signaling may play an essential role controlling the transition of neuronal progenitors from a proliferative condition towards neuronal differentiation.