Role of GDNF/GFRa1 on neuroal stem cell development

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

Congreso; Annual meeting of the Society of Neuroscience; 2015

The cerebral cortex is among the most complex of all biological structures and the major site of higher cognitive functions specific to our species. During its development, progenitors proliferate in the ventricular zone and then migrate into the cortical layers where they differentiate into specific cell types. These timed sequence of the developmental process is controlled by an intrinsic cellular program, as well as extrinsic environmental cues. Because impaired regulation of progenitors causes many developmental disorders, it is crucial to understand the mechanisms underlying the behavior of progenitors, including migration, proliferation, and differentiation.Glial cell line-derived neurotrophic factor (GDNF) was originally discovered because of its ability to promote the survival of ventral midbrain dopaminergic neurons. GDNF signals by binding to the glycosylphosphatidylinositol-anchored receptor GFRα1 in complex with the canonic receptor tyrosine kinase Ret or the neural cell adhesion molecule (NCAM). GDNF and its receptor GFRα1 have been reported to have an essential role in cell migration and differentiation in the peripheral and central nervous system. In particular, GDNF can stimulate migration of precursors of inhibitory interneurons in the rostral migratory stream, and the cerebral cortex. However the role of GDNF/ GFRα1 in the forebrain development is still unknown.In the present work, we set out to investigate new roles of GDNF in the developing nervous system. In particular, we analyzed the role of GDNF and its receptor GFRαa1 in the development of cortical precursors. Our results indicate that GDNF and GFRα1, control the transition of neuronal glutamatergic progenitors from a proliferative state towards neuronal differentiation, in a Ret-independent manner. We show that GDNF is able to arrest the proliferation of cultured neuronal precursors induced by bFGF promoting neuronal morphological differentiation. The physiological relevance of this system in cell cycle arrest and differentiation of neuronal precursors is being elucidated in GFRα1-conditional mice.