Barbara A. Barres

Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture

The signaling mechanisms that control the survival of CNS neurons are poorly understood. Here we show that, in contrast to PNS neurons, the survival of purified postnatal rat retinal ganglion cells (RGCs) in vitro is not promoted by peptide trophic factors unless their intracellular cAMP is increased pharmacologically or they are depolarized by K+ or glutamate agonists. Long-term survival of most RGCs in culture can be promoted by a combination of trophic factors normally produced along the visual pathway, including BDNF, CNTF, IGF1, an oligodendrocyte-derived protein, and forskolin. These results suggest that neurotransmitter stimulation and electrical activity enhance the survival of developing RGCs and raise the question of whether the survival control mechanisms of PNS and CNS neurons are different.

Hepatocyte Growth Factor/Scatter Factor Is an Axonal Chemoattractant and a Neurotrophic Factor for Spinal Motor Neurons

In the embryonic nervous system, developing axons can be guided to their targets by diffusible factors secreted by their intermediate and final cellular targets. To date only one family of chemoattractants for developing axons has been identified. Grafting and ablation experiments in fish, amphibians, and birds have suggested that spinal motor axons are guided to their targets in the limb in part by a succession of chemoattractants made by the sclerotome and by the limb mesenchyme, two intermediate targets that these axons encounter en route to their target muscles. Here we identify the limb mesenchyme-derived chemoattractant as hepatocyte growth factor/scatter factor (HGF/SF), a diffusible ligand for the c-Met receptor tyrosine kinase, and we also implicate HGF/SF at later stages as a muscle-derived survival factor for motoneurons. These results indicate that, in addition to functioning as a mitogen, a motogen, and a morphogen in nonneural systems, HGF/SF can function as a guidance and survival factor in the developing nervous system.

Does oligodendrocyte survival depend on axons

BACKGROUND We have shown previously that oligodendrocytes and their precursors require signals from other cells in order to survive in culture. In addition, we have shown that about 50% of the oligodendrocytes produced in the developing rat optic nerve normally die, apparently in a competition for the limiting amounts of survival factors. We have hypothesized that axons may control the levels of such oligodendrocyte survival factors and that the competition-dependent death of oligodendrocytes serves to match their numbers to the number of axons that they myelinate. Here we test one prediction of this hypothesis - that the survival of developing oligodendrocytes depends on axons. RESULTS We show that oligodendrocyte death occurs selectively in transected nerves in which the axons degenerate. This cell death is prevented by the delivery of exogenous ciliary neurotrophic factor (CNTF) or insulin-like growth factor I (IGF-1), both of which have been shown to promote oligodendrocyte survival in vitro. We also show that purified neurons promote the survival of purified oligodendrocytes in vitro. CONCLUSION These results strongly suggest that oligodendrocyte survival depends upon the presence of axons; they also support the hypothesis that a competition for axon-dependent survival signals normally helps adjust the number of oligodendrocytes to the number of axons that require myelination. The identities of these signals remain to be determined.

New views on synapse—glia interactions

Although glial cells ensheath synapses throughout the nervous system, the functional consequences of this relationship are uncertain. Recent studies suggest that glial cells may promote the formation of synapses and help to maintain their function by providing nerve terminals with energy substrates and glutamate precursors.

What the fly's glia tell the fly's brain.

Introduction The brain is an astonishingly complex organ that records, responds and adapts to experience-all the result of simple interactions between neurons and glia. Whereas the neurons interconnect to form electrically active circuits, the role of glia is a mystery (Figure 1). Do glial cells just provide a passive framework that supports, nourishes, and insulates neurons, or, in addition, do glial cells play more active roles in signaling and plasticity? The importance of glia is suggested by their increase in number during evolution; glial cells constitute 25%, 65%, and 90% of cells in the Drosophila, rodent, and human brain, respectively. How can the unknown, and perhaps unimagined, functions of a cell type be determined? Studies of gliausing histology, immunostaining, tissue culture, and electrophysiology have led to a number of hypotheses about what glial cells do (Barres, 1991). For instance, glial cells may guide developing neurons and their axons to their targets, may promote the survival and differentiation of neurons, may form the blood-brain barrier, and may help regulate the extracellular concentrations of ions and neurotransmitters. The problem has been how to test these hypotheses definitively. Would it matter if there were no glia? In two landmark studies, the labs of Corey Goodman and of Yoshiki Hotta have selectively eliminated glial cells in vivo to explore how the brain develops and functions without them (Hosoya et al., 1995; Jones et al., 1995). They have identified a Drosophila gene, glial cells missing (gem), that encodes a novel nuclear protein that is required for glial cell fate determination and is transiently expressed early during the development of nearly all glia. In the absence of functional GCM protein, nearly all glial cells differentiate into neurons, whereas ectopic expression of gem in immature neurons or their precursor cells transforms them into glia (Figure 2). Thus, gem functions as a binary genetic switch that determines whether developing neural cells will become neurons or glia. Although loss-of-function homozygousgcm mutations are ultimately lethal to thedeveloping embryos, much of neural development is completed prior to their death, allowing a direct examination of the role of glia in neural development. In addition, mutation of another Drosophila glia-specific homeodomain protein, REPO, has also been found to eliminate many glia (Campbell et al., 1994; Halter et al., 1995; Xiong and Montell, 1995). In this minireview, we will summarize the insights into glial function that fly genetics have recently provided; the implications of the gem genetic switch for understanding how neural cell fate is controlled are discussed elsewhere (Anderson, 1995). Minireview

Retinal development: Communication helps you see the light

Recent studies suggest that interactions between neurons, glial cells and endothelial cells are critical in determining the structure of the retina and the optic nerve. Dysregulation of these interactions can lead to disruption of retinal architecture and impairment of vision.

Neural regeneration: Extending axons from bench to brain

Many studies have shown that myelin in the central nervous system strongly inhibits the regeneration of axons, so it comes as a surprise to discover that adult neurons transplanted into the brain rapidly extend their axons through myelinated pathways.

Neurotrophins moving forward

When neurons innervate their target cells, its well known that they transmit signalling molecules known as neurotrophins to these cells, in a process known as anterograde transport. For the first time, one group has now shown that retrograde transport can also occur — that is, the same neurotrophins are carried from the target cell to the neuron. These interactions are probably crucial for sculpting the developing brain into its final, functional form.