Role of the GDNF / GFRa1 system in the development and maturation of neuronal precursors

Abstract

During development, neural stem cells (NSCs) and their derivative progenitor cells give rise to all the neurons of the central nervous system, with only a few neurogenic zones remaining active in the adult. 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. The transition of proliferative progenitor cells to fully differentiated neurons is controlled by an intrinsic cellular program, as well as extrinsic environmental cues, such as neurotrophic factors. Neurotrophic factors play key roles in the maintenance and survival of different neuronal populations in the peripheral and central nervous system. Glial cell line-derived neurotrophic factor (GDNF) was originally discovered because of its ability to promote the survival of ventral midbrain dopaminergic neurons, those affected in Parkinson´s disease. GDNF signals by binding to the glycosylphosphatidylinositolanchored receptor GFRα1 in complex with the canonic receptor tyrosine kinase Ret or the neural cell adhesion molecule (NCAM). The aim of this thesis was to identify and analyze new roles of GDNF and its receptors during the proliferation and differentiation of neural progenitors both in the developing as in the adult nervous system. To start analyzing the role of GDNF and its receptor GFRα1 in cortical neurogenesis, GFRα1 expression was analyzed in the forebrain during development. It was found that GFRα1 is expressed from an early developmental stage, increasing its levels in inverse proportion to the levels of the mitogenic factor, bFGF. Furthermore, it was observed that the expression levels of GFRα1 correlated with neuronal differentiation of cortical precursors. The addition of GDNF to cultures of neuronal precursors decreased the proliferation rate of the progenitors and increased morphological differentiation of postmitotic neurons. Analysis of animals deficient for GFRα1 in neuronal precursors show lower neuritic complexity of cortical neurons, and an increase in proliferation rate of progenitors in vivo. Taken together, these results show that GDNF may be playing an antagonistic role to bFGF on cortical precursors. This would indicate that the GDNF / 11 GFRα1 system plays an essential role in regulating the proliferative condition and the differentiation of cortical progenitors. On the other hand, the role of the GDNF/GFRα1 system in adult neurogenesis was analyzed. It was found that GFRα1 is highly expressed in the dentate gyrus of the hippocampus, a neurogenic zone. Adult born granule neurons derived from mice deficient in GFRα1 in neuronal progenitors of the adult hippocampus showed lower neuritic complexity than those observed in control mice neurons. Ablation of GFRα1 in adult hippocampal progenitors was associated with behavioral deficits, providing new insights into its physiological importance. In conclusion, in this manuscript new physiological roles of GDNF and its receptor, GFRα1, were identified. Cortical and adult progenitors share certain characteristics and differ in others, however the GDNF/GFRα1 system may act as a general regulator coordinating neuronal differentiation