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First published online 11 December 2002
doi: 10.1242/jcs.00223

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Programmed cell death in the developing inner ear is balanced by nerve growth factor and insulin-like growth factor I

Laura M. Frago^1,*, Susana Cañón¹, Enrique J. de la Rosa², Yolanda León^1,3,, and Isabel Varela-Nieto^1,

¹ Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain
² Centro de Investigaciones Biológicas, CSIC, Velázquez 144, 28006 Madrid, Spain
³ Departamento de Biología (Fisiología Animal), Universidad Autónoma de Madrid, Carretera de Colmenar km. 15, Cantoblanco, 28049 Madrid, Spain
^* Present address: Unidad de Investigación, Departamento de Pediatría-UAM, Hospital Universitario Niño Jesús, Av. Menéndez Pelayo 65, 28009 Madrid, Spain

Author for correspondence (e-mail: yleon{at}iib.uam.es)

Accepted 14 October 2002

Nerve growth factor induces cell death in organotypic cultures of otic vesicle explants. This cell death has a restricted pattern that reproduces the in vivo pattern of apoptosis occurring during inner ear development. In this study, we show that binding of nerve growth factor to its low affinity p75 neurotrophin receptor is essential to achieve the apoptotic response. Blockage of binding to p75 receptor neutralized nerve-growth-factor-induced cell death, as measured by immunoassays detecting the presence of cytosolic oligonucleosomes and by TUNEL assay to visualize DNA fragmentation. Nerve growth factor also induced a number of cell-death-related intracellular events including ceramide generation, caspase activation and poly-(ADP ribose) polymerase cleavage. Again, p75 receptor blockade completely abolished all of these effects. Concerning the intracellular pathway, ceramide increase depended on initiator caspases, whereas its actions depended on both initiator and effector caspases, as shown by using site-specific caspase inhibitors. Conversely, insulin-like growth factor I, which promotes cell growth and survival in the inner ear, abolished apoptosis induced by nerve growth factor. Insulin-like growth factor cytoprotective actions were accomplished, at least in part, by decreasing endogenous ceramide levels and activating Akt. Taken together, these results strongly suggest that regulation of nerve-growth-factor-induced apoptosis in the otocysts occurs via p75 receptor binding and is strictly controlled by the interaction with survival signalling pathways.

Key words: p75 neurotrophin receptor (p75^NTR), Ceramide, Caspase activation, Cell survival, Otic vesicle, Ceramide-1-phosphate

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