Research

     CONTROL OF NERVE CELL
       DIFFERENTIATION

     GENETIC DETERMINANTS
       OF NEURONAL NUMBER

     PATTERNED NERVE CELL
       DISTRIBUTIONS IN THE
       BRAIN

     RPE SIGNALLING AND
       AXONAL MISROUTING AT
       THE OPTIC CHIASM

Control of Nerve Cell Differentiation

        Horizontal cells are inhibitory interneurons with laterally oriented dendrites that stratify within the outer plexiform layer of the retina, where they make contact with the pedicles of cone photoreceptors. The dendrites of adjacent horizontal cells overlap one another, so that multiple horizontal cells converge upon individual pedicles. Because the population of horizontal cells is assembled as a regular array, or “mosaic”, these features of dendritic overlap and convergence ensure that the network of these cells provides a uniform coverage of the retinal surface. The principles underlying this organization are conserved across a large variation in horizontal cell density in different strains of mice, suggesting that cell-cell interactions, rather than cell-intrinsic instructions, must play a role in achieving the network properties of the horizontal cell mosaic. The developmental mechanisms establishing these features of horizontal cell morphology, connectivity and patterning are undefined, but recent studies in our laboratory have indicated that interactions between neighboring horizontal cells, as well as interactions with afferents, play a role.

        For example, the intercellular spacing of horizontal cells is largely independent of genetic background, being near-perfectly predicted by local horizontal cell density. Dendritic field area compensates for this variation in intercellular spacing, maintaining a uniform dendritic coverage across these strains of mice, suggesting that neighboring horizontal cells constrain one another’s dendritic growth. Functional dendritic overlap for the horizontal cells is achieved anatomically at the pedicles, where the number of dendritic terminals from neighboring horizontal cells changes, reciprocally, during development, suggestive of a competitive interaction between horizontal cells. The afferents also play a role in defining horizontal cell morphology, as their elimination prior to innervation compromises dendritic branching and prevents terminal formation altogether. These results suggest that afferent and homotypic interactions participate in the generation of horizontal cell morphology, dendritic overlap, convergence and connectivity, but the mechanisms mediating these intercellular interactions remain to be defined. Our goal is to understand the cellular, molecular and genetic determinants of this patterning and connectivity in the population of horizontal cells.