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

Patterned Nerve Cell Distributions in the Brain

        The past two decades have witnessed great strides in our understanding of the developmental mechanisms producing the mature architecture and connectivity of the brain, at both the cellular and molecular level. For example, we now appreciate how cell-cycle kinetics and exit-decisions are regulated, and how this influences the proliferative phase expanding the wall of the neural tube, establishing the size of a founder-population of cells making up a particular structure. We also have some understanding of the early patterning that occurs within the developing CNS, regulating gene expression to move regions of tissue down various differentiation pathways. Likewise, we now know that cell fate decisions, while being biased or constrained by such patterning events affecting progenitor cells, are also determined by environmental interactions with other cells and their associated inductive and permissive signals. Such neuroblasts in turn migrate via a variety of mechanisms that include cell-surface or secreted proteins that may inhibit, support, attract or repel young neurons. The environmental determinants of nerve cell differentiation in turn have been identified for various populations of neurons, and the signals and their reception which mediate neurite-outgrowth and pathfinding are being understood in increasingly molecular detail. The interactions between the pre- and post-synaptic membrane are also being elucidated as synaptogenesis occurs, and how those rudimentary interactions bootstrap themselves into mature synapses or lead to their elimination. Cell death also contributes to the final organization of a brain structure, controlled by afferent, target and glial interactions that modulate signaling pathways for cell death.

        Doubtless the full complexities of these issues remain to be elucidated, but we can now provide a description of the approximate “life-history” of a given brain structure and entertain reasonable hypotheses about the mechanisms that bring about each of those various developmental changes participating in its formation.

     

        What is notably lacking, however, is any description of the spatial relationship between neurons within a volume of brain tissue, and the determinants of their intercellular spacing. For instance, a population of neurons arising from the ventricular zone must then migrate to, and settle within, a nuclear or cortical domain, but the determinants of their positioning within those structures is unknown. At one extreme, a population of neurons settling in a structure may be packed so densely that they are positioned side-by-side, and there is no mystery to their positioning. At the other, many types of nerve cell comprise a minority of the local population and the average spacing between them is conspicuous. Even a majority cell-type may comprise only a small proportion of the structural volume, the remainder being occupied by the neuropil, glial processes and vascular network.

        How these cells in such populations become distributed relative to one another, or relative to other cells occupying the same volume, is rarely addressed. We do not know, for instance, whether higher-order patterning is present, much like a rough or distorted lattice, or whether such cells are essentially randomly distributed within the volume, constrained only by the physical size of one another. We may know quite a bit about the dendritic morphology of these cells, and can make inferences about the relationship between the morphology of an individual cell and how a population of those cells should be distributed in order to maximize a uniform dendritic coverage within the structure, but little concrete evidence exists to relate the one to the other. We are currently developing tools  for the purpose of accomplishing this goal, namely, to quantify the spatial relationship between cells in three-dimensional space, and from that, to develop models of their spacing that can be tested experimentally.