de Bellard Lab

1. Understand neural crest migration as modulated by the Tumor-suppressor Slit.

Neural crest cells are a multipotent cell lineage that delaminates from the dorsal neural tube of developing vertebrate embryos and subsequently undergo an epithelial to mesenchymal transition enabling stationary cells to actively migrate to distant areas. Neural crest EMT is valuable to study since the same process occurs in cancer metastasis. Mechanisms controlling migration of neural crest cells are not fully understood. Slit2 is a chemorepellant guidance molecule that stimulates the motility of trunk neural crest cells and repels them from the developing gut. Recently published research has identified Slit2 as a tumor suppressor molecule. The individual connections of neural crest cell EMT and Slit2 in cancer metastasis led us to believe that there may be a link between Slit expression and proper neural crest cell migration.

2. Identify molecules that determine the specific migratory pathways decisions by neural crest cells.

The neural crest is a migratory population of cells that gives rise to a wide range of cell types in the peripheral nervous system of vertebrate embryos. It has been shown that neural crest cells migrate along specific pathways throughout the embryo. The reason for such specificity is not fully known, although recent studies have described axon pathfinding repellants (ephrinB2, SemaIIIa, Slit2, etc.) to also be chemorepellents of neural crest cells. The goal of this study was to find which other molecules are capable of guiding the neural crest and their close derivatives, Schwann cell precursor cells (SCPC’s). Only certain neurotrophins were tested whose presence in the embryo spatiotemporally matches the migrating neural crest. Experiments by live imaging of cells exposed to a linear chemical gradient, and other methods suggest that: a) neural crest cells and SCPC’s are attracted to glial cell line-derived neurotrophic factor (GDNF), macrophage migration inhibitory factor (MIF), and Heregulinβ1; b) neural crest cell migration is stimulated in the presence of GDNF, Heregulinβ1, and nerve growth factor (NGF). These preliminary data suggest that neural crest cells and SCPC’s use a variety of neurotrophic factors as guiding cues during their extensive migration in the embryo.

3. Look at neural crest markers through evolution in sharks, snakes and lampreys.

The neural crest is responsible for the formation of the peripheral nervous system and head structures. We are looking into the evolution of neural crest in elasmobranches and other non-mammalian organisms by looking at the pattern of expression of genes like Sox10, Seraf, Sox2, etc during early development.

4. Increase knowledge about glial cell evolution among earliest metazoans.

The nervous system is comprised of neurons and glial cells. Much is known about neurons, their evolution and development; however, the “history” of glial cells remains elusive. Most of the research on the nervous system has focused on neurons, though glial cells are fundamental in the formation and maintenance of complex nervous systems. The nervous system in the earliest invertebrates (Cnidarians and Ctenophores) is very simple, but already at the next group of organisms in evolution, the Platyhelminthes, organized ganglia that have clearly defined glial cells are observed. Knowledge about the appearance of glial cells during evolution is far from settled: there is still no clear agreement among scientists about which organisms have or do not have true glial cells among the earliest taxa (ranging from Cnidarians thorough Platyhelminthes). There has been some recent work on identifying genes that are specific for glia, however, none so far has approached the study of these set of genes across evolution. True understanding of brain evolution needs proper understanding of glial evolution as well. This proposal will bridge this important knowledge gap as well as improve and contribute to a deeper understanding of the evolution of nervous systems. The main scientific question this proposal will ultimately answer is: Is the appearance of glial cells a critical event in nervous system evolution?