Poster Sessions

Neu-23

Guhan Nagappan

G. Nagappan, B. Lu

Transcriptional gene regulation by the BDNF pro-fragment

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays a pivotal role in the vertebrate nervous system development, synapse plasticity and in various cognitive brain functions in adulthood. Alterations in BDNF levels have been implicated in developmental, neurodegenerative, and psychiatric disorders as well as in substance abuse. Like all neurotrophins, BDNF is synthesized as a precursor protein (proBDNF), and subsequently cleaved by protease(s) to generate the pro-fragment and mature BDNF (mBDNF). While the role of mBDNF in synaptic plasticity is well established and the biological function(s) of proBDNF is beginning to emerge, the function of the BDNF pro-fragment, or pro-fragments of any of the neurotrophins after their cleavage from pro-neurotrophins is unknown. The pro-fragment was suggested to facilitate proper folding of the mature domain in the precursor protein, but generally believed to be degraded after its removal from their precursor pro-neurotrophins. Conversely, neuropeptide research suggests that peptides generated by the cleavage of their precursors serve as novel ligands with distinct functions. Consistently, using a pro-fragment specific antibody generated by a novel strategy, we show that the intact BDNF pro-fragment is not only present in the rat/mouse brain, but specifically localized in the neuronal nucleus suggesting a novel biological function for the BDNF pro-fragment. Both yeast two-hybrid, and co-immunoprecipitation analysis revealed the nuclear orphan receptor/transcriptional repressor, NR1D2 (Nuclear Receptor subfamily 1, group D, member 2) as a specific interactor of the BDNF pro-fragment. Interestingly, our recent study showed that neuronal activity not only induce proBDNF secretion, but also regulate its cleavage to mBDNF and pro-fragment by the regulated secretion of the protease, tissue Plasminogen Activator (tPA). The activity-dependent control of proBDNF cleavage, together with nuclear translocation of extracellular pro-fragment suggests its role in gene transcription and synapse plasticity. Our study provides the first example of how neuronal activity could regulate proteolytic cleavage of an extracellular ligand (proBDNF) followed by nuclear translocation (BDNF pro-fragment) to regulate gene expression.