CONICET | Buscador de Institutos y Recursos Humanos

During development, neural stem cells and their derivative progenitor cells give rise to all the neurons of the nervous system. The transition of proliferative progenitor cells to fully differentiated neurons is controlled by intrinsic programs, as well as extrinsic environmental cues, such as neurotrophic factors. In this work, we studied the role of glial cell line-derived neurotrophic factor (GDNF) and its receptor, GFRa1, during the proliferation and differentiation of cortical neural precursors cells (CNPs) both in the developing cortex.We show that GDNF and GFRa1 are expressed in the mice neocortex during the period of cortical neurogenesis. We show that GDNF through its receptor GFRa1 inhibits self-renewal capacity of mouse CNPs induced by FGF2, promoting neuronal differentiation. While GDNF leads to decreased proliferation of cultured CNPs, selective ablation of GFRa1 in glutamatergic cortical precursors enhances its proliferation. Moreover, analysis of conditional GFRa1-knockout mice shows an increase in the number of cycling cells during cortical development.We also show that GDNF treatment of CNPS resulted in a marked increase in neuronal population and promoted morphological differentiation even in the presence of FGF2. Analysis of newborn conditional GFRa1-deficient mice shows a reduction in dendritic length in a subpopulation of cingulate cortical neurons in vivo. This result is in agreement with our previous findings indicating that the GDNF/GFRa1 complex plays a crucial role in the development of hippocampal dendritic arbors (1). Together, these results indicate that GDNF/GFRa1 signaling plays an essential role in regulating the proliferative condition and the differentiation of CNPs to cortical or hippocampal neurons. The evidence obtained gives new opportunities to study the function of GDNF in neurodevelopmental diseases characterized by cognitive deficits.