In development of the nervous system, form follows function. In order to achieve a functional network, neurons must wire correctly during development and maintain that general architecture for the lifetime of the organism. Improper sculpting of the nervous system may result in developmental disorders such as mental retardation, and there is increasing evidence that some age-related neurodegenerative conditions, such as Alzheimer's disease, co-opt developmental sculpting programs. This proposal examines the mechanistic basis for developmental competition for survival. It is now appreciated that neuronal competition for survival is mediated by limiting amounts of survival factors secreted from neuronal targets. Furthermore, it is known that as neurons compete, those that eventually win the competition for survival improve their ability to respond to this survival factor (sensitization) while actively secreting a factor that expedites the death of weaker neighbors (punishment). It is easy to imagine how pathologies such as Lou Gerhig's or Parkinson's disease might use these developmental programs to disassemble the nervous system. This proposal examines the mechanisms underlying developmental competition for survival. In particular, we will address the following questions: How Is Neuronal Trophic-Factor Sensitivity Regulated? A primary mechanism for modulating signaling sensitivity is through the regulation of signaling endosome stability. We have identified coronin-1 as an NGF-dependent factor, which has been shown to be involved in endosome stability in the context of pathogen-host interaction (tuberculosis and leprosy). An immediate future direction is to examine the influence of coronin-1 on the trophic factor (NGF) signaling endosome using loss-of-function models in conjunction with novel techniques to visualize this endosome. We will also assess the role of coronin-1 in acquisition of competitive advantage and NGF-dependent survival using in vitro and in vivo gain- and los-of-function approaches. This work will provide insight into the molecular underpinnings of competition, and into an understudied mode of receptor tyrosine kinase regulation. What Is the Relationship Between the Protection and Punishment Signaling Pathways? During developmental competition for survival, a population of neurons simultaneously undergoes sensitization and punishment. Within each individual neuron, it is the imbalance between these signaling pathways that determines whether the cell ultimately lives or dies. This proposal examines how this imbalance is established.

Public Health Relevance

Delineating the mechanisms underlying developmental competition for neuronal survival should represent a new way to think about nervous system patterning. Moreover, this line of investigation may reveal clues about the etiology and progression of pathologies that remodel the nervous system, such as ALS or Alzheimer's.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS072388-03
Application #
8442873
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Mamounas, Laura
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$326,012
Indirect Cost
$98,735
Name
University of Virginia
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Barford, Kelly; Keeler, Austin; McMahon, Lloyd et al. (2018) Transcytosis of TrkA leads to diversification of dendritic signaling endosomes. Sci Rep 8:4715
Cheng, Irene; Jin, Lucy; Rose, Lucy C et al. (2018) Temporally restricted death and the role of p75NTR as a survival receptor in the developing sensory nervous system. Dev Neurobiol 78:701-717
Keeler, Austin B; Suo, Dong; Park, Juyeon et al. (2017) Delineating neurotrophin-3 dependent signaling pathways underlying sympathetic axon growth along intermediate targets. Mol Cell Neurosci 82:66-75
Sipe, L M; Yang, C; Ephrem, J et al. (2017) Differential sympathetic outflow to adipose depots is required for visceral fat loss in response to calorie restriction. Nutr Diabetes 7:e260
Barford, Kelly; Deppmann, Christopher; Winckler, Bettina (2017) The neurotrophin receptor signaling endosome: Where trafficking meets signaling. Dev Neurobiol 77:405-418
Martorella, M; Barford, K; Winkler, B et al. (2017) Emergent Role of Coronin-1a in Neuronal Signaling. Vitam Horm 104:113-131
Wheeler, Michael A; Smith, Cody J; Ottolini, Matteo et al. (2016) Genetically targeted magnetic control of the nervous system. Nat Neurosci 19:756-761
Suo, Dong; Park, Juyeon; Young, Samuel et al. (2015) Coronin-1 and calcium signaling governs sympathetic final target innervation. J Neurosci 35:3893-902
Wheeler, Michael A; Heffner, Danielle L; Kim, Suemin et al. (2014) TNF-?/TNFR1 signaling is required for the development and function of primary nociceptors. Neuron 82:587-602
Suo, Dong; Park, Juyeon; Harrington, Anthony W et al. (2014) Coronin-1 is a neurotrophin endosomal effector that is required for developmental competition for survival. Nat Neurosci 17:36-45

Showing the most recent 10 out of 13 publications