Development of the brain is a highly ordered process with a number of important steps. Cells must be directed to the proper fate in the ventricular zone, migrate to the appropriate laminar location once born and establish connectivity with their targets. Many patients with epilepsy or congenital brain malformations have morphologic abnormalities consistent with defects in the control of cell fate, neuronal migration or axon guidance in the developing telencephalon. My research focuses on several distinct aspects of the regulation of these events using the developing hippocampus and cortex as the model systems. We are using a broad array of embryologic and molecular genetic techniques to understand these processes in the normal developing state as well as in animals with developmental anomalies. In addition, we are interested in applying these approaches to improving the prospects of enhancing endogenous pools of neural stem cells to regenerate after developmental or other insults.
Control of tangential migration in cortical development // Meningeal-cortical interactions during development // Control of cell fate in neural precursors // Development of the dentate gyrus
1. Control of tangential migration in cortical development.
We found that Cxcl12, produced by the meninges is required for the normal laminar position of Cajal-Retzius neurons as they migrate tangentially to cover the cortex. We have now determined as well that Cxcl12 has a similarly important role in regulating the laminar organization of interneuron migration from the ganglionic eminences to the developing cortex. In mice
with either null or condition mutations in CXCR4, the best characterized Cxcl12 receptor, the normal laminar organization of these cells into two layers (a superficial and a deep layer) is severely perturbed and the cells chaotically enter the forming cortical plate too early in gestation. We are in the process of characterizing the developmental and behavioral consequences of these defects using conditional mutant mice where CXCR4 is removed selectively in developing cortical interneurons (these mice survive while the null mutants die at birth for non-neurologic reasons). We are extending these studies using a recently developed mouse reagent that allows conditional inactivation of all Gi-coupled signaling that will allow us to elucidate the potential roles for other Gi-coupled signaling pathway in the tangential migration of both Cajal-Retzius cells and GABAergic interneurons.
2. Meningeal-cortical interactions during development
During cortical development the meninges serve as an understudied source of signaling molecules potentially regulating migration and differentiation of cortical neurons. We have demonstrated that the production of Cxcl12 by the meninges is required for normal positioning of an important group of developmental pioneer neurons. In the course of these studies, we realized that the intimate association of the developing meninges and cortex makes it likely that the meninges act more widely to provide a host of developmental influences for the cortex. This has led to expansion of this area of research in two directions. We are characterizing the phenotype of mutants that have primary meningeal defects and secondary cortical defects. This will allow us to elucidate the ways that meningeal development influences cortical development. Preliminarily, we have found that, as expected, the meninges play an important role in producing the extracellular matrix lining the superficial
cortex. More interestingly, we have noted evidence for an earlier gestational role in controlling the proliferative dynamics of the
ventricular zone. We believe that the intimate association of radially oriented neuroepithelial cells with one process contacting the ventricular surface and the other attached to the meninges are ideally situated to receive mitotic inputs from factors produced by the meninges. We are in the process of examining the potential meningeally produces molecular cues
regulating VZ proliferation. This has also led to a new interest in the lab focused on determining the developmental events that regulate the development of the meninges during early cortical development.
3. Control of cell fate in neural precursors
During development multipotential neural stem cells are influenced to restrict their developmental potential and to generate particular differentiated cellular offspring neurons, astrocytes and oligodendrocytes. Much of our work is designed to study the behavior of these cells in situ in developing systems such as the dentate gyrus and cortex. We have also been developing a new area of research over the last few years using more simplified systems to study the direct effects of signaling molecules on the behavior of neural precursors. This work has focused on determining the shared and distinct direct transcriptional
targets of known cell fate regulatory molecules that act during differentiation of neural stem cells. This approach has now successfully allowed us to begin to elucidate the network of downstream signaling events that are activated after forced differentiation of neural stem cells toward neuronal or oligodendrocyte lineages. In particular, we are focusing on the
regulation of oligodendrocyte specification by members of the SoxE transcription factor family.
4. Development of the dentate gyrus
The dentate gyrus has a unique developmental plan requiring the migration of multipotential neural precursors from the developmental neurogenic niche (the ventricular zone) to a secondarily induced neurogenic zone (the subgranular zone of the dentate granule cell layer). We have been engaged in long-term studies examining the roles of signaling molecules in maintaining
and organizing the neurogenic organization of the dentate gyrus. Published studies from my lab have demonstrated that Wnts and SDF1 are key regulators of this process and ongoing studies are using conditional genetic approaches to dissect the roles of these pathways (and others) in dentate development and adult neurogenesis. We believe that the dentate gyrus is an important model system allowing the study of how adult stem cell niches are constructed during development by migration of stem cells and crafting of the local environment to ensure their continued multipotentiality. Ongoing work in the lab is examining the role of CXCR4 signaling and other Gi-coupled GPCR signaling in regulating dentate stem cell self-renewal in the dentate gyrus and potential molecular interactions between these pathways and Shh-signaling in the dentate.
