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National Heart, Lung, and Blood Institute
Developmental Neurobiology Section

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Control of Neuronal Growth by Astrocytes

Both development of the neuron and the neuronal response to injury are shaped by interactions between neurons and glial cells. Current research focuses on the role of astrocytes, the major glial cell in the central nervous system. Astrocytes normally provide a favorable environment for neurons, e.g., during development they promote neuronal migration and process outgrowth. However, after injury, astrocytes become reactive and form a major part of the "glial scar" that forms around the injury site that inhibits regeneration. Identifying the specific gene products that are responsible for the permissive or inhibitory actions of astrocytes as well as their mechanism of action is a major effort underway in this laboratory. The ultimate goal is to promote neuronal regeneration by preventing these changes in astrocytes, adding permissive molecules to astrocytes, or causing neurons to ignore the inhibitory cues.

The Role of the Extracellular Matrix in Neuronal Pathfinding

We are evaluating the mechanisms by which astrocytes provide directional cues for neurons. We have focused on the behavior of a growing growth cone as it encounters a boundary. Guidance is provided by molecules that impart directional, as opposed to growth-modifying, cues to axons. These molecules reside within the extracellular matrix, where growing neurons will encounter them. Some molecules are permissive for growth and guidance, while other molecules are inhibitory. One class of inhibitory astrocyte-derived guidance molecules in the extracellular matrix are the family of chondroitin sulfate proteoglycans (CSPGs). We believe that repair of the injured nervous system will be increased by harnessing the permissive cues, and blocking the inhibitory ones. Understanding the signals that control this behavior is thus a necessary step to achieving our goals.

See a Quick Time Movie of a Growth Cone at a Boundary

How chondroitin-4 sulfated proteoglycans guide neurons

We have investigated the role of sulfation of chondroitin glycosaminoglycan (GAG) chains in neuronal guidance. Our studies have revealed a selective inhibitory action of GAG chains due to their decoration sulfate in the 4-position of N-acetyl-galactosamine. Elimination of only a few sulfates in the chain abrogates biological activity. This suggests the existence of a "sulfation code" by which GAG chains signal to neurons. We are conducting experiments to determine this sulfation code. Moreover, reduction of 4-sulfation may then be a novel way to improve regeneration after spinal cord injury. In addition, experiments are in progress to identify the receptors which mediate CSPG actions on neurons.

Signal Transduction Mechanisms in Neuronal Guidance

One major area is to understand the signals that are initiated within a neuron after encountering these cues, and then how to modify them to persuade the neuron to grow across an inhibitory boundary. Axonal turning is dependent upon rearrangement of the cytoskeleton, first in the growth cone and then in the growing axon. Actin and tubulin are the two major cytoskeletal proteins. Fluorescent speckle microscopy can localize movement of cytoskeletal proteins in living neurons. The end-binding protein EB3 localizes to areas of microtubule polymerization. By expressing fluorescently-tagged EB3 in living neurons, we can follow the polymerization of tubulin as neurons encounter boundaries and in response to molecules that promote axonal growth. Similar techniques will allow the localization of the other cytoskeletal proteins in these situations.

See a Quick Time Movie of RFP-EB3 Speckles in a Cerebellar Granule Neuron

Dr. Herbert Geller, Chief
Developmental Neurobiology Section, NHLBI, NIH
Building 10, Room 6D18, 10 Center Drive, MSC-1754
Bethesda, MD 20892
Email: gellerh@nhlbi.nih.gov

Cardiovascular Health Partners
Healthy People 2010

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