Associate Professor, Biology
- BS, Biomedical Sciences/Chemistry, Western Michigan University
- PhD, Biochemistry & Molecular Biology, Purdue University
- Postdoc, Developmental Neuroscience, John Hopkins University
Biochemistry, Biotechnology, Cell and Developmental Biology, Development, Metabolism, Molecular Biology, Neuroscience, Stem Cells & Regeneration
Elucidating and Understanding the Mechanisms Underlying Nervous System Development
Background and Summary of Previous Findings:
Neural development involves competition at many levels, whether it be axons innervating a target or synapses refining a connection. Over 50 years ago, Viktor Hamburger and Rita Levi-Montalcini put forth the first hypothesis explaining competition in the PNS. Their hypothesis posited that neuronal survival during development is dependent on a limited supply of target-derived trophic factors.
For a target-derived factor to influence neuronal survival, its signal must get from the tip of the innervating axon back to the neuronal cell body, a particularly daunting task in the long neurons of the PNS. Using sympathetic neurons as a model system, we and others have directly demonstrated that these long-distance signals are transduced via a retrograde signaling endosome carrying target-derived nerve growth factor (NGF) and its cognate receptor, TrkA. Once this signaling endosome arrives at the cell body, the activated TrkA receptor initiates pro-survival events.
The hypothesis of Hamburger and Levi-Montalcini explains neuronal competition at the population level; the supply of NGF at the target is only sufficient to support survival of a certain number of neurons. At the level of the individual cell however, the basis of neuronal competition for survival is less clear. If all cells are capable of endosomal retrograde signaling, what makes one cell more competitive, more successful at taking up NGF and therefore more likely to survive, than its neighbor? Is it due to varying concentrations of trophic factor, and subsequently, differences in magnitude of signal transduction? Or, alternatively, are there factors that give some neurons a competitive advantage?
We recently found that neuronal competition at the individual cell level involves a complex combination of events (Deppmann et al., Science). We used mathematical modeling, biochemical, and genetic approaches to show that, in the PNS, the likelihood of neuronal survival is critically dependent on a sensitization process initiated by target innervation and strengthened by a series of positive-feedback loops. We found that in addition to initiating expression of survival factors, the retrogradely transported NGF-TrkA signaling complex also increases expression of TrkA, thereby increasing the magnitude of NGF-TrkA pro-survival signaling. We also discovered that the duration of NGF-TrkA pro-survival signaling is variable, and regulated in an NGF-dependent manner. The exact mechanism of this regulation is unknown.
NGF also influences a complex protection/punishment mechanism affecting neuronal survival. We found that, in sympathetic neurons, NGF signaling induces a cell to increase secretion of BDNF and NT4 which, via p75 signaling, can kill or "punish" neighboring sympathetic neurons in a paracrine manner. High NGF-TrkA signaling protects neurons from this punishment signal while low NGF-TrkA signaling leaves cells vulnerable. This finding is consistent with the 1972 theory of Meinhardt and Gierer suggesting that self-activation and lateral inhibition underlie pattern formation. We feel that these three elements--target-initiated sensitization, protection from punishment, and punishment--are essential for the rapid and robust competition implicit within the neurotrophic factor hypothesis.
Current Projects In the Lab
There are several projects that are available which will be scaled for undergrad students, grad students, or post-docs. Without getting bogged down with too much detail, here are a few potential projects available for people to work on. Of course these will evolve as we move forward.
1. Examine neuronal competition for survival in complex populations of neurons.
Our previous work exploited the relative simplicity of the sympathetic nervous system to delineate the rules for competition. Other populations of neurons, such as those in the dorsal root ganglia, are more complex. We hypothesize that in these more complex systems the sensitization process is likely to remain very similar to what we observe in the sympathetic nervous system. Punishment signaling may function differently however, as the punishment cues identified in sympathetic neurons--BDNF-induced p75 signaling for instance--would actually have trophic effects in some neighboring TrkB positive neurons.
2. Delineate signaling underlying protection and punishment cross-talk
This has been a long-standing issue in the trophic factor field, however very little is known. We have developed several promising leads as to how these signaling pathways communicate with one another. Understanding how these antagonistic programs communicate with each other not only has implications for the development of the nervous system, but may also lead to insights into pathologies such as neuroblastoma or neurodegeneration.
3. Examine if signaling programs involved in competition for survival are also involved in competition for synaptic connectivity
After a developmental critical period, neurons no longer rely on target derived trophic factor for survival even though its availability and signaling persist into adulthood. If this signaling is not functioning as a pro-survival cue, what is it doing after this critical period? Synapse formation is an attractive candidate for this since it occurs after competition for survival. Therefore, this project will center around determining whether this signaling is important for synapse formation.
4. Examine the role of novel target derived neurotrophin regulated genes in developmental processes such as competition, axon extension, axon branching, changes in metabolism, and acquisition of neurotransmitter phenotype.
We previously performed a microarray analysis to identify genes regulated by target derived trophic factor in vivo. There are still 100's of interesting genes yet to be characterized in these processes. We have already begun characterizing genes that are important for cytoskeletal re-arrangement, signaling endosome function, and axon guidance.
5. Determine if re-engagement of developmental competition programs can participate in diseases of the nervous system.
The notion of pathologies co-opting developmental programs has been proposed in certain types of cancer as well as in complications in nerve regeneration. While there has been significant progress made identifying causative factors underlying neurodegenerative pathologies, the mechanism by which the pathology spreads to asymptomatic neurons in diseases such as Parkinson's or ALS has been largely unexplored.
To learn more about potential research projects,
visit my lab webpage.