Study of the role of Cripto in neural development and diseases

Neurodegenerative diseases include a broad array of conditions that involve progressive functional loss and death of brain cells. The number of cases is rapidly growing worldwide with increasing life expectancies. For this reason, finding new biomarkers and therapeutic targets for neurodegenerative diseases is a goal of extreme urgency. Recently Cripto, the founding member of EGF-CFC protein family, a key factor during development and tumorigenesis, has been found related to neurodegenerative processes in a macaque models of neuroAIDS. Cripto is a GPI-anchored protein involved in many signaling pathways (among them Nodal/GDF and MAPK), that can be cleaved and released in the extracellular compartment and in human serum. Very few data on Cripto expression in embryonic and adult nervous system are available, but most expression correlates with pathological conditions, both neurodegenerative diseases and brain tumors. Our purpose is to investigate the role of Cripto in the progression of neural pathologies. To this aim, we are performing an expression profile analysis of Cripto during neural development and in neurodegenerative mouse models and a functional analysis by studying the effects of Cripto ectopic expression on neural progenitors. Our results show for the first time an increased expression of Cripto and the activation of its pathway coupled to neurodegeneration induced by neurotoxin intracranial injection. Moreover, transiently overexpression of Cripto membrane-anchored protein or its soluble form in embryonic neurospheres suggested that Cripto is able to impair neural terminal differentiation. We are now constructing a virus for the stable expression of Cripto in neural stem cells in order to study in detail its effect on self-renewal and differentiation. Our studies will contribute to address the role of Cripto in neural development and degeneration and its relevance as biomarker and/or therapeutic target in neural pathologies.