This problem is taken to extraordinary lengths in the human brain, where 100 billion neurons and glia follow rules to form the right connections with one another, in order to create consciousness and thought. What are these rules, and where are they written?
The system: We are using a tiny worm called C. elegans to answer these questions.
Its cells come together by following remarkably strict rules. Consequently, each individual worm ends up with the same number of cells, in the same places, with the same shapes, and forming the same cell-cell attachments. Because these animals are transparent and easy to manipulate genetically, they provide a powerful system for identifying the rules of cellular development.
We are focused in particular on the development of sensory neurons and glia: first, because these cell types are inherently interesting, and second — from a practical standpoint — because their shapes are easily visualized and relate to their function in an obvious way; these cells are not essential; and genetic tools are available that allow us to manipulate them in a highly targeted way, often altering just a single neuron or glial cell.
Our approach: We are trying to understand how cells pick the right partners — "selective cell adhesion" — and how cells get the right shapes — specifically, how cells sense and respond to mechanical force.
Selective cell adhesion How does a cell recognize which partners to attach to? We are studying this in the context of (1) neuron-glia attachments and (2) dendrite fasciculation.
1. Neuron-glia attachments. First, we are trying to understand what makes one glial cell different from another. We have identified mutants in which animals are missing some glial types, and have too many of other glial types. These mutants will help us understand how glial diversity is generated — the first step in understanding how a neuron recognizes which glial cell to partner with.
2. Selective fasciculation. Throughout our nervous system, axons and dendrites are organized into bundles called fascicles. C. elegans sensory dendrites always fasciculate with the same partners and, amazingly, occupy a stereotyped position within the bundle, as if each dendrite adheres with specific neighboring dendrites. We are identifying the molecules responsible for this remarkable degree of order.
Mechanical forces and morphogenesis Cell shape is ultimately the product of mechanical force pulling and pushing on the cell membrane. We are studying how cells sense and respond to force in the context of epithelial and non-epithelial interactions.
1. ZP domain proteins and epithelial integrity ZP domain proteins are nearly universal components of epithelia, but no shared function for them has been found. We identified a ZP domain protein that keeps dendrite endings anchored in place while neuronal cell bodies migrate away, causing the dendrites to elongate by stretch. This is leading to a surprising parallel between neuron-glia interactions and epithelial mechanics.
2. Stretching cells by embryo elongation We have also identified a separate class of dendrite that grows by stretch, but does not require ZP domain proteins. Instead, these dendrites attach to neighboring glia and allow the overall forces of embryo elongation to stretch them to their mature length. We are studying how this neuron-glia attachment allows the dendrites to stretch.