Regulation of nervous system wiring by small heat shock proteins
My laboratory studies how genetics and environment combine to regulate wiring of the nervous system. We are specifically interested in how small heat shock proteins (sHSPs) regulate development of the retinal projection to higher visual centers in the zebrafish (Danio rerio). Their roles in other systems suggest that they are likely to be important in several different contexts: that of normal development, in the context of environmental stress, and in a genetically sensitized background.
Background and rationale
Wiring of the nervous system occurs largely through the activity of growth cones, specialized structures at the leading edges of axons that migrate to their ultimate targets. This can be an extremely complicated task, as the growth cones of millions - or billions - of neurons must navigate through complex environments to one or more targets. It is only through precise regulation of growth cone behavior that a functioning nervous system is eventually formed. sHSPs are known to regulate actin dynamics in migrating cells. As regulation of the actin cytoskeleton underlies growth cone migration, and as sHSPs are present in differentiating neurons, sHSPs are also likely to regulate normal growth cone behavior. We are currently testing this possibility.
In addition to regulating normal actin cytoskeletal dynamics, HSPs are known to protect cells from the effects of environmental insult, such as elevated temperature, UV light, ischemia, alcohol, and heavy metal toxicity, as well as mutations in the genetic background. Therefore, defects in sHSP function frequently result in increased sensitivity to environmental or genetic stressors. We are therefore testing whether sHSPs protect retinal ganglion cell (RGC) growth cones in the context of environmental stress, as well as in the context of the retinotectal pathfinding mutant astray (shown at right).
Shown at right are confocal projections of the optic tract in 5 day old zebrafish labeled with the fluorescent tracer DiI: On the left is a wild-type zebrafish. The RGC axon fascicle emerges from the opposite side of the brain and the axons project to the optic tectum (OT), where they de-fasciculate, arborize, and terminate. On the right is an astray mutant (ast). Many RGC axons defasciculate and misroute early in their pathway, resulting in a disorganized visual projection.
Some of the main advantages of using zebrafish as a system to study nervous system is its small size and transparency (at least in embryonic stages). We take advantage of these features to make movies of living growth cones as they navigate to their targets. To see some really cool growth cone movies, click here.
