The long-range goal of the proposed studies is to determine the cellular, genetic and molecular interactions that underlie trigeminal sensory ganglion development. The trigeminal sensory ganglion is the primary group of sensory nerves in the vertebrate head and mediates touch, temperature and pain sensations. It is formed from neural crest and placodal precursors that migrate to a shared assembly site. These two subpopulations segregate to different regions of the ganglion and differentiate into stimulus-specific neuronal subtypes. Malformations or injuries of the trigeminal sensory ganglion are associated with neuralgia, a recurrent facial pain condition. Despite its important role, very little is known about how the trigeminal sensory ganglion develops. This proposal focuses on the mechanisms by which trigeminal sensory neurons are recruited to the ganglion assembly site and how the two precursor populations sort to two distinct domains of the ganglion. Using zebrafish as a model, we will analyze neuron assembly and segregation by combining in vivo imaging of fluorescently labeled neuronal precursors with embryological and genetic manipulations.
In Specific Aim 1, we will determine how chemokine signaling guides neurons to the assembly site. We will test the hypotheses that chemokine signaling is intrinsically long-range but becomes restricted to a short-range signal by the environment.
In Specific Aim 2, we will determine how cell adhesion mediates sorting of neurons into different regions of the ganglion. We find that cell adhesion receptor expression divides the ganglion into different regions. We will test the hypothesis that neurons sort to different regions of the ganglion based on their adhesive properties. Lastly, we will ask how chemokine guidance and cell adhesion cooperate to organize the assembling ganglion. With these studies, we hope not only to provide insights into how neurons are organized into clusters, but also shed light onto the mechanisms underlying trigeminal neuropathies that can contribute to painful disease conditions afflicting humans.
Neurons in the nervous system are organized into layers and clusters. How this complex structure forms is unclear. We are using the trigeminal sensory ganglion in zebrafish as a model to address this question. In this proposal, we ask how chemokine signaling and cadherin cell adhesion receptors work together to assemble neurons into a cluster.
|Fuentes, Fernando; Reynolds, Eric; Lewellis, Stephen W et al. (2016) A Plasmid Set for Efficient Bacterial Artificial Chromosome (BAC) Transgenesis in Zebrafish. G3 (Bethesda) 6:829-34|
|Wang, John; Knaut, Holger (2014) Chemokine signaling in development and disease. Development 141:4199-205|
|Lewellis, Stephen W; Nagelberg, Danielle; Subedi, Abhi et al. (2013) Precise SDF1-mediated cell guidance is achieved through ligand clearance and microRNA-mediated decay. J Cell Biol 200:337-55|
|Venkiteswaran, Gayatri; Lewellis, Stephen W; Wang, John et al. (2013) Generation and dynamics of an endogenous, self-generated signaling gradient across a migrating tissue. Cell 155:674-87|
|Lewellis, Stephen W; Knaut, Holger (2012) Attractive guidance: how the chemokine SDF1/CXCL12 guides different cells to different locations. Semin Cell Dev Biol 23:333-40|