Neurotrophins regulate critical cell fate decisions, by modulating neuronal survival, differentiation, and morphology during development. Neurotrophins are initially synthesized as a precursor, or proneurotrophin, which can be cleaved to a mature form that mediates survival and differentiation actions via the Trk receptor tyrosine kinases. However, proneurotrophins, including proBDNF, exert independent cell fate decisions by activating the p75 receptor and sortilin, to mediate cell death. In preliminary studies, we have identified two new components of the proneurotrophin receptor complex, and provide evidence that through the utilization of different co-receptors, that proneurotrophins can initiate distinctive signaling pathways, to induce neuronal apoptosis, or to acutely induce growth cone pruning, resulting in decreased dendritic complexity in vivo. During the prior funding cycle, we have also identified new signaling partners downstream of p75, real time imaging techniques to quantitatively measure acute remodeling of neuronal processes, and a new conditional knock-in mouse to evaluate the effects of proBDNF at the biochemical level, in neuronal cultures and in in vivo paradigms. Here we propose three interrelated aims to molecularly dissect the mechanisms by which proneurotrophins regulate distinct cellular fates of apoptosis, or acute cytoskeletal remodeling. First, we will examine the receptors complexes that bind to proBDNF and proNGF, and determine how the choice of receptor subunit ultimately dictates biological responses. Specifically, we will identify how p75 differentially partners with distinct sortilin family members and with a related receptor component, NRH2. We will then test how these receptor complexes engage different signaling pathways to promote apoptosis or acute morphological responses that result in growth cone collapse. Second, we will dissect two signaling pathways downstream of p75, mediated by PKC activation or GTPase inactivation, which initiate pruning responses to proneurotrophins, using real-time quantitation of growth cone movement. Lastly, we will utilize our newly generated inducible proBDNF knock-in mouse to identify the critical """"""""windows of vulnerability"""""""" in which proBDNF mediates apoptotic or remodeling outcomes in the developing hippocampus, and in peripheral sympathetic neurons. By regulating proBDNF expression in early development, or in the adult, we will directly test whether the effects of proBDNF are limited to perinatal ages, to sculpt neuronal morphology and to regulate the generation of distinct subpopulations of neurons, or are utilized throughout adulthood to continue to prune connectivity and modulate synaptic transmission.

Public Health Relevance

Neurotrophins, including brain derived neurotrophic factor (BDNF) have pleiotropic effects on neural development and synaptic plasticity that underlie circuit formation and cognitive function;even modest changes in BDNF levels lead to behavioral changes in humans or mouse models. BDNF is first synthesized as a precursor, proBDNF, that induces cell death, or pruning of neuronal processes, actions distinct from the survival effects of mature BDNF. Here, we use technical advances of new receptor components and signaling pathways activated by proBDNF, and a mouse model to dissect proBDNF actions in the developing brain. These studies permit us to determine how proBDNF regulates neuronal cell fate, and the regressive events of naturally occurring neuronal death and pruning of dendrites, to establish appropriate neuronal circuitry.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS030687-20
Application #
8274685
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Mamounas, Laura
Project Start
1993-01-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
20
Fiscal Year
2012
Total Cost
$362,294
Indirect Cost
$104,950
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Ma, Qian; Yang, Jianmin; Milner, Teresa A et al. (2017) SorCS2-mediated NR2A trafficking regulates motor deficits in Huntington's disease. JCI Insight 2:
Harward, Stephen C; Hedrick, Nathan G; Hall, Charles E et al. (2016) Autocrine BDNF-TrkB signalling within a single dendritic spine. Nature 538:99-103
Ma, Qian; Yang, Jianmin; Li, Thomas et al. (2015) Selective reduction of striatal mature BDNF without induction of proBDNF in the zQ175 mouse model of Huntington's disease. Neurobiol Dis 82:466-477
Anastasia, Agustin; Barker, Phillip A; Chao, Moses V et al. (2015) Detection of p75NTR Trimers: Implications for Receptor Stoichiometry and Activation. J Neurosci 35:11911-20
Song, Minseok; Giza, Joanna; Proenca, Catia C et al. (2015) Slitrk5 Mediates BDNF-Dependent TrkB Receptor Trafficking and Signaling. Dev Cell 33:690-702
Lee, Bridgin G; Anastasia, Agustin; Hempstead, Barbara L et al. (2015) Effects of the BDNF Val66Met Polymorphism on Anxiety-Like Behavior Following Nicotine Withdrawal in Mice. Nicotine Tob Res 17:1428-35
Irmady, Krithi; Jackman, Katherine A; Padow, Victoria A et al. (2014) Mir-592 regulates the induction and cell death-promoting activity of p75NTR in neuronal ischemic injury. J Neurosci 34:3419-28
Yang, Jianmin; Harte-Hargrove, Lauren C; Siao, Chia-Jen et al. (2014) proBDNF negatively regulates neuronal remodeling, synaptic transmission, and synaptic plasticity in hippocampus. Cell Rep 7:796-806
Hempstead, B L (2014) Deciphering proneurotrophin actions. Handb Exp Pharmacol 220:17-32
Fulmer, Clifton G; VonDran, Melissa W; Stillman, Althea A et al. (2014) Astrocyte-derived BDNF supports myelin protein synthesis after cuprizone-induced demyelination. J Neurosci 34:8186-96

Showing the most recent 10 out of 52 publications