REGULATION OF PROLIFERATION AND SELF-RENEWAL OF RODENT AND HUMAN NEURAL STEM CELLS BY VAX1

Recently stem cell biology has emerged as a bridge between the traditional field of cell biology and developmental genetics. There are great expectations regarding the therapeutic use of neural stem cells (NSCs) and particularly adult NSCs (ANSCs) as a treatment for neurodegenerative diseases. However, the use of NSCs for therapeutic purposes requires an appropriate knowledge of the environmental- and genetic mechanisms regulating their basic functions, namely proliferation and their capacity to generate mature brain cells for transplantation. Several genes playing such critical roles during the embryonic and early post-natal life have been discovered and there are indications that some of them might maintain a similar role also in adult brain stem cells. One of those genes is Emx2, that has recently been correlated to the regulation of ANSCs under the auspices of the Telethon Foundation. Vax genes (Vax1 and Vax2) are closely related to Emx genes and regulate proliferation and differentiation of retinal progenitor cells. We have preliminary data indicating that Vax1 is expressed in stem cells of the adult CNS and in ANSCs, and that its absence is related to defects in proliferation/migration of NSCs. Thus, we propose to study the role of Vax1 in regulating proliferation and maturation in the embryonic, post-natal and adult NSCs. Understanding the genetic mechanisms at the basis of stem cell biology is essential to implement studies and trials for cell replacement therapies. One possible therapeutic approach that may emerge from this study may lie on the development of pharmacological strategies through which one can alter the proliferation, mobilization and/or specific differentiation of ANSCs, either in vivo or ex vivo. Moreover, in this project we will extend the analysis of Vax1 function to human NSCs with obvious advantages for the development of combined cell/gene-based therapeutic approaches for neurodegenerative disorders.