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.
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.
|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|
|Sokolowski, Jennifer D; Gamage, Kanchana K; Heffron, Daniel S et al. (2014) Caspase-mediated cleavage of actin and tubulin is a common feature and sensitive marker of axonal degeneration in neural development and injury. Acta Neuropathol Commun 2:16|
|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|