Genetic dissection of EphA receptor signaling dynamics during retinotopic mapping.

Retinal ganglion cells (RGCs) project axons from their cell bodies in the eye to targets in the superior colliculus of the midbrain. The wiring of these axons to their synaptic targets creates an ordered representation, or "map," of retinal space within the brain. Many lines of experiments have demonstrated that the development of this map requires complementary gradients of EphA receptor tyrosine kinases and their ephrin-A ligands, yet basic features of EphA signaling during mapping remain to be resolved. These include the individual roles played by the multiple EphA receptors that make up the retinal EphA gradient. We have developed a set of ratiometric "relative signaling" (RS) rules that quantitatively predict how the composite low-nasal-to-high-temporal EphA gradient is translated into topographic order among RGCs. A key feature of these rules is that the component receptors of the gradient--in the mouse, EphA4, EphA5, and EphA6--must be functionally equivalent and interchangeable. To test this aspect of the model, we generated compound mutant mice in which the periodicity, slope, and receptor composition of the gradient are systematically altered with respect to the levels of EphA4, EphA5, and a closely related receptor, EphA3, that we ectopically express. Analysis of the retinotopic maps of these new mouse mutants establishes the general utility of the RS rules for predicting retinocollicular topography, and demonstrates that individual EphA gene products are approximately equivalent with respect to axon guidance and target selection.journal articleresearch support, n.i.h., extramuralresearch support, non-u.s. gov't2011 Jul 13importe

A simple model can unify a broad range of phenomena in retinotectal map development

A paradigm model system for studying the development of patterned connections in the nervous system is the topographic map formed by retinal axons in the optic tectum/superior colliculus. Starting in the 1970s, a series of computational models have been proposed to explain map development in both normal conditions, and perturbed conditions where the retina and/or tectum/superior colliculus are altered. This stands in contrast to more recent models that have often been simpler than older ones, and tend to address more limited data sets, but include more recent genetic manipulations. The original exploration of many of the early models was one-dimensional and limited by the computational resources of the time. This leaves open the ability of these early models to explain both map development in two dimensions, and the genetic manipulation data that have only appeared more recently. In this article, we show that a two-dimensional and updated version of the XBAM model (eXtended Branch Arrow Model), first proposed in 1982, reproduces a range of surgical map manipulations not yet demonstrated by more modern models. A systematic exploration of the parameter space of this model in two dimensions also reveals richer behavior than that apparent from the original one-dimensional versions. Furthermore, we show that including a specific type of axon-axon interaction can account for the map collapse recently observed when particular receptor levels are genetically manipulated in a subset of retinal ganglion cells. Together these results demonstrate that balancing multiple influences on map development seems to be necessary to explain many biological phenomena in retinotectal map formation, and suggest important constraints on the underlying biological variables

A Computational Model of Granule Cell Migration and Purkinje Cell Primary Dendrite Selection during Cerebellar Development

This project aims to investigate the interrelationship between primary dendrite selection of Purkinje cells and migration of their pre-synaptic partner granule cells during cerebellar development. During development of the cerebellar cortex, each Purkinje cell grows more than three dendritic trees, among which a primary tree is selected to develop further, whereas others completely retract. Experimental studies suggested that this selection process is coordinated by physical and synaptic interactions with granule cells. However, technical limitations hinder a continuous observation on multiple populations of the cells. To reveal the mechanism underlying this selection process, we constructed a computational model of dendritic development and granule cell migration, using a new computational framework, NeuroDevSim. Comparisons of the resulting morphologies from the model demonstrated the roles of the selection stage in regulating the growth of the selected primary trees. This thesis presents the first computational model that simultaneously simulates growing Purkinje cells and the dynamics of granule cell migration, revealing the role of physical and synaptic interactions upon dendritic selection. Development of the model is expected to provide new insights in the development of neonatal Purkinje cells and help to track down how cerebellar cortex develops into a normal or abnormal structure.Okinawa Institute of Science and Technology Graduate Universit