The intracellular portion of GITR enhances NGF-promoted neurite growth through an inverse modulation of Erk and NF-κB signalling

• Main Authors: Laura McKelvey, Humberto Gutierrez, Giuseppe Nocentini, Sean J. Crampton, Alun M. Davies, Carlo R. Riccardi, Gerard W. O’keeffe
• Format: Article
• Language: English
• Published: The Company of Biologists 2012-08-01
• Series: Biology Open
• Subjects: GITR; NF-κB; NGF; Growth; Neurite; Neuron
• Online Access: http://bio.biologists.org/content/1/10/1016

Summary NF-κB transcription factors play a key role in regulating the growth of neural processes in the developing PNS. Although several secreted proteins have been shown to activate NF-κB to inhibit the growth of developing sympathetic neurons, it is unknown how the endogenous level of NF-κB activity present in these neurons is restricted to allow neurite growth to occur during their normal development. Here we show that activation of the glucocorticoid-induced tumour necrosis factor receptor (GITR) inhibits NF-κB activation while promoting the activation of Erk in developing sympathetic neurons. Conversely, inhibition of GITR results in an increase in NF-κB dependent gene transcription and a decrease in Erk activation leading to a reduction in neurite growth. These findings show that GITR signalling can regulate the extent of sympathetic neurite growth through an inverse modulation of Erk and NF-κB signalling, which provides an optimal environment for NGF-promoted growth.