Neurotrophins in the Regulation of Cellular Survival and Death Claire Ceni, Nicolas Unsain, Michele P. Zeinieh, and Philip A. Barker Abstract The neurotrophins play crucial roles regulating survival and apoptosis in the developing and injured nervous system. The four neurotrophins exert profound and crucial survival effects on developing peripheral neurons, and their expres- sion and action is intimately tied to successful innervation of peripheral targets. In the central nervous system, they are dispensable for neuronal survival during development but support neuronal survival after lesion or other forms of injury. Neurotrophins also regulate apoptosis of both peripheral and central neurons, and we now recognize that there are regulatory advantages to having the same molecules regulate life and death decisions. This chapter examines the biological contexts in which these events take place and highlights the specific ligands, receptors, and signaling mechanisms that allow them to occur. Keywords Proneurotrophins • p75NTR • Sortilin • Retrograde signaling • Tumor cells • Apoptosis • Death domains • NF-kB • Interleukin-1 receptor associated kinase (IRAK) • RIP2 • Receptor-interacting serine/Threonine-protein kinase 2 (RIP2) • Neurotrophin receptor interacting factor (NRIF) • Neurotrophin receptor-interacting MAGE homolog (NRAGE) 1 Introduction The regulation of cell survival and death is a key aspect of the establishment of functional neuronal circuits. A remarkable feature of the developing vertebrate nervous system is that, for most populations, an excess of neurons is produced and C. Ceni • N. Unsain • M.P. Zeinieh • P.A. Barker (*) Centre for Neuronal Survival, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, QC, Canada H3A 2B4 e-mail: phil.barker@mcgill.ca G.R. Lewin and B.D. Carter (eds.), Neurotrophic Factors, Handbook of Experimental Pharmacology 220, DOI 10.1007/978-3-642-45106-5_8, # Springer-Verlag Berlin Heidelberg 2014 193