Programmed cell death is a critical process for normal development and tissue homeostasis. While the basic programme of execution of apoptosis is conserved, distinct regulatory signals have been described depending on the cell type and developmental stage. Particularly interesting are the opposite actions displayed by nerve growth factor (NGF), which acts either as a survival factor or as a death-inducing factor. A coherent understanding of the regulation of programmed cell death during development requires a co-ordinated study of some of the multiple signals acting on the cells. We are interested in the molecular mechanisms by which these signals initiate and pattern the vertebrate inner ear. IGF-1 is a member of a family of structurally related genes that have pleiotropic actions on embryonic cells. In vitro culturing and knock-out analysis with mice have determined that IGF-1 is critical for the proper development and maturation of the inner ear. IGF-1 stimulates the generation of lipidic second messengers, activates the Raf/mitogen-activated protein kinases cascade and increases AP-1 and PCNA levels leading to cell growth and survival. In contrast, NGF, after binding to p75 low affinity receptors, increases ceramide levels and activates Jun N-terminal kinase and caspase-3, in a process that regulates apoptotic cell death. In this context, we have explored the interactions between the pathways activated by IGF-1 to prevent apoptosis and those activated by NGF to induce cell death. We propose that the dynamic balance between levels of ceramide metabolites and the consequent regulation of Akt phosphorylation are important factors that determine whether a cell survives or dies.

This work was supported in part by grants from Dirección General de Investigación, Ciencia y Tecnolog’a (PM99-0111).