Neuronal and glial cell biology

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Neuronal and glial cell biology Editorial overview Pietro De Camilli* and Rhona Mirskyt Addresses *Department of Cell Biology, Howard Hughes Medical Institute, Yale University School of Medicine, 295 Congress Avenue, New Haven, Connecticut 06510, USA; e-maik [email protected] fDepartment of Anatomy and Developmental Biology, University College London, Gower Street, London WC! E 6BT, UK; e-maik [email protected] Current Opinion in Neurobiology 1997, 7:595-597 http://biomednet.com/elecref/0959438800700595 © Current Biology Ltd ISSN 0959-4388

Abbreviations NCAM neuralcell adhesion molecule NMDA N-methyI-D-aspartate PSA polysialic acid

Introduction

The nervous system is one of the most specialized tissues of the body. Yet, the evolutionary conservation that is emerging between highly specialized nervous system functions and housekeeping processes characteristic of all cells is impressive. An important focus of earlier research on the cell biology of the nervous system was the identification of proteins unique to the nervous system, in an effort to understand its unique functions. Now, in an almost complementary approach, the comparison of corresponding functions in neuronal and non-neuronal cells is generating great excitement in the field. Thus, neuronal cell biology not only continues to be a specialized field to which general information emerging from other areas of cell biology can be applied, but it is also becoming a frontier in which pioneering studies on a variety of fundamental mechanisms, well beyond the field of excitability and signal transduction, can be carried out. For example, the exo-/endocytic recycling of synaptic vesicles at the synapse has proved to be a powerful experimental model for studying fundamental mechanisms in vesicular transport. Studies of the transport of macromolecules and organelles along neurites have provided insights into general aspects of intracellular motilit3: In addition, the unique morphology of neurons provides a system in which the role of intrinsic and extrinsic factors in determining cell morphology can be fruitfully analyzed.

of membrane trafficking [2]. This issue focuses on a few selected topics in neuronal and glial cell biology that have produced particularly interesting recent advances and that have not been covered in a systematic fashion in recent reviews.

Neuronal cell biology The origin of neuronal shape

This section starts with an update by Higgins, Burack, Lein and Banker (pp 599-604) on the mechanisms involved in the generation of the complex neuronal shape. It is now well established that the property of generating two distinct set of processes, axons and dendrites, is an intrinsic property of neurons, which can be recapitulated in vitro. The elucidation of the molecular mechanisms underlying the emergence, growth and development of these processes is only beginning, but some leads have emerged. For example, there is now growing evidence' that the mechanisms that control cell polarity in yeast have an important role in neurite outgrowth and in the regulation of the spatial and temporal parameters of this process. These mechanisms involve GTPases of the Rho/Rac/Cdc42 family. There is also evidence that some of the mechanisms underlying polarized sorting of membrane and cytosolic proteins are similar in neurons and other polarized cells, such as epithelial cells. However, important differences discussed in the review caution against assuming that the interesting similarities that have already emerged between the apical membrane domain of epithelial cells and the axonal membrane of n e u r o n s - - a n d between the basolateral domain of epithelial cells and the dendritic arbor of neurons--will be applicable to all aspects of the generation of neuronal polarity. An important recent breakthrough has been the identification of secreted factors that have powerful and dramatic effects on the development of the dendritic tree. These findings suggest mechanisms, aside from cell-cell contact, by which glial cells can control neuronal shape. Factors that are implicated in the control of axonal growth are also discussed in the review by Mason and Sretavan (see below). Molecular motors

Many important aspects of neuronal cell biology have been reviewed extensively in other recent issues of the Current Opinion series. For example, several ptesynaptic and postsynaptic aspects of synaptic transmission, as well signalling mechanisms, have been recently reviewed in the 'Signalling mechanisms' issue of Current Opinion in Neurobio/ogy [1]. In addition, a recent issue of Current Opinion in Cell Biology covered many important aspects

The next two reviews in this section summarize current information on the two main types of molecular motors that mediate the vectorial transport of macromolecules and organelles within the neuronal cytoplasm: microtubular motors and actin-based motors (i.e. the myosins). The heterogeneous composition of the neuronal cytoplasm clearly implies the existence of mechanisms that selectively regulate transport of distinct organelles and

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macromolecules. However, the multiplicity of molecular motors, and of their isoforms generated by alternative splicing, exceeds expectations. Hirokawa (pp 605-614) covers the field of microtubular motors, with emphasis on the function of the kinesin superfamily. Although the impressive list of kinesin molecules and their properties gives us glimpses into the mechanisms that control the differences in motility between organelles, the mechanisms that mediate the selective interactions of these various motors with distinct sets of cargo remain a topic for future investigation. T h e review by Hirokawa also provides a comprehensive discussion of 'slow' axonal transport of cytoskeletal proteins, a field that is still poorly understood and very controversial. While early work in this area had suggested that microtubules and neurofilaments travel down the axons as assembled polymers, recent studies support the alternative hypothesis that cytoskeletal proteins travel as small oligomers along microtubular tracks. T h e massive explosion of information on myosin motors is reviewed by Hasson and Mooseker (pp 615-623). Myosin motors appear to be involved in the most diverse cellular functions, ranging from cell motility to control of cell shape and to organelle transport. Even though the multiplicity of myosins and their different tissue distributions provide a basis for this multiplicity of function, satisfactory functional information is still missing for many of the myosin genes. Interesting insights have come from mutations affecting myosin genes in a variety of organisms, including humans. Their review discusses in some detail the fascinating field of the role of myosin in sensory organs responsible for hearing, balance and vision. Vesicular traffic Vesicular traffic at the synapse was reviewed recently in the Signalling mechanisms (June 1997) issue of Current Opinion in Neurobiology [1]. T h e review by Wu and Bellen (pp 624-630) discusses the contribution of Drosophila genetics to this field. While genetic research has led other areas of neuronal cell biology, the genetic approach has lagged behind biochemistry and biophysics in the study of presynaptic mechanisms. Classical and reverse genetics studies, however, are now progressing at a rapid pace both in Drosophila and C. elegans. So far, these studies have primarily helped to further elucidate the function of genes in the synaptic vesicle cycle already identified by other experimental approaches. T h e field is now ripe for the full exploitation of genetics, not only to elucidate interaction cascades of known genes, but also to identify new genes. Important breakthroughs in the field of presynaptic function are also rapidly emerging from genetic studies in mice. Imaging of macromolecules and organelles A precise understanding of cellular functions is crucially dependent upon the possibility of acquiring dynamic

as well as static information. Technical advances in video microscopy techniques and the rapidly expanding collection of readily available fluorescent probes are greatly expanding our possibilities in this area. A most powerful tool, which has already found many applications in neurobiologs; is the green fluorescent protein (GFP) from the jelly fish Aequorea victoria. T h e review by Lippincott-Schwartz and Smith (pp 631-639) focuses on the application of imaging techniques to the study of organelle dynamics in living cells. Transfection of cells with genes encoding GFP fusion proteins, combined with the application of photobleaching techniques, has resulted in an impressive body of novel information about membrane dynamics along the exocytic and endocytic pathway: Although these studies have been primarily carried out in non-neuronal cells, they open new avenues for the study of organelle transport in neurons. N e u r a l cell b i o l o g y In the nervous system, neurons never stand alone, and interactions between neurons and gila are of crucial importance in guiding the development of the nervous system and in maintaining its functions once mature. This theme is explored in different ways in three reviews. Modulation of neuronal-glial interactions Adhesion molecules have been discussed in several earlier issues of Current Opinion in Neurobiology, particularly those focusing on Neuronal and glial cell biology. In this issue, this subject is explored from another angle, Kiss and Rougon (pp 640-646) discuss the particular importance of the polysialylated form of neural cell adhesion molecule (NCAM) in the development and maintenance of the nervous system. T h e polysialylation of NCAM is unique in the nervous system, and the identification and cloning of the enzymes that transfer polysialic acid (PSA) to NCAM will probably result in major advances in understanding the control of expression, biosynthesis and function of PSA-NCAM in the near future. Various regulators of PSA-NCAM expression are emerging, including electrical activity. Activation of N M D A receptors also appears to control expression of PSA-NCAM in both neurons and oligodendrocyte precursors.

Earlier evidence suggested that PSA-NCAM attenuated adhesive interactions between axons. More recent evidence suggests it may modulate cell-surface interactions by allowing dynamic changes in the shape or movement of cells or of their processes. T h e role of PSA-NCAM in branching and fasciculation is more complex than originally envisaged. In peripheral nerves, it appears to promote defasciculation, whereas in at least two CNS systems, the optic tract and hippocampus, it appears to promote fasciculation. This emphasizes the importance of context, as presumably the final outcome is determined by the combined effect of several adhesion molecules. Recent experiments indicate the potential importance of PSA-NCAM in the process of learning and mem-

Editorial overview De Camilli and Mirsky

ory, perhaps through its ability to promote structural remodelling at synapses: removal of PSA from NCAM prevents induction of long-term potentiation (LTP) and long-term depression (LTD) in hippocampal slice cultures; and NCAM knock-out mice show reduced induction of LTP and deficits in spatial learning. Understanding the mechanisms by which this occurs will be a major challenge. Neuronal-glial interactions in the optic chiasm

T h e development of the optic chiasm in mice provides a good model system for exploring the complex interactions between neurons and gila that occur during axon pathfinding in the nervous system. It is also likely to provide insights into the relationship between the targeting of retinal ganglion axons and the establishment of binocular vision. The review by Mason and Sretavan (pp 647-653) underlines the importance of both glial and neuronal populations in establishing the paths chosen by both ipsilateral and contralateral retinal ganglion cell axons as they find their way to their targets in the embryonic brain, and in establishing the position of the optic chiasm on the developing hypothalamus. Ventral midline radial glial cells, which appear to have properties in common with spinal cord floor plate cells, support axon outgrowth but do not appear to direct pathfinding. By analogy with Drosophila, where ventral midline cells mediate commissure formation in the CNS, they may however provide information for guidance of later axons as they segregate into ipsi- and contralateral pathways. Early generated neurons are found in the same general location, and studies indicate that they have a role in establishing the optic chiasm, in providing a posterior boundary along which ingrowing retinal ganglion cell axons track and in influencing the morphology of the radial glia. Indirect evidence suggests that sonic hedgehog (Shh), so important in the development of the spinal cord, may also be involved in the induction of these neurons, in combination with other proteins. Comparisons of chiasm development in mice, which have binocular vision, and zebrafish, which do not, are likely to be informative. Early generated neurons do not exist at the zebrafish ventral midline, whereas incoming axons have only limited contact with radial glia, again pointing to the importance of these two populations in providing an environment in which putative ipsi- and contralateral axons can receive signals prior to making the decision of whether or not

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to cross the ventral midline. Some of the genes that may influence the patterning of the ventral hypothalamic region are also beginning to be identified. The vital role of lipids in the myelin sheath T h e m y e l i n sheath s u r r o u n d i n g large d i a m e t e r axons is

formed by oligodendrocytes in the CNS and Schwann cells in the PNS, and represents one of the most dramatic examples of the importance of interactions between one cell type and another. Transgenic approaches have been extensively used to dissect the contribution of the major myelin proteins to the properties of the sheath, while lipids, the other major component of the sheath membrane, have been relatively neglected. Stoffel and Bosio (pp 654-661) review the structure and properties of the major myelin membrane galactolipids and describe how they are synthesized. The recent cloning of the major synthetic enzyme UDP-galactosyl-ceramide galactosyl transferase, the last step in the synthesis of the major myelin lipid galactocerebroside, has led to the generation of knock-out mice deficient in three vital galactolipids: galactocerebroside itself, its derivative sulfatide and galactodiglyceride. These mice have a dramatic phenotype, with shivering, seizures, progressive paralysis and ensuing death. Somewhat surprisingly; the myelin sheaths generated by Schwann cells in the PNS of these mice look normal ultrastructurally. Even in the CNS, the sheaths are relatively normal in the internodal regions; however, at the nodal regions, some abnormalities are apparent. The nervous system abnormalities were revealed by measuring axonal conduction, which was abnormally slow: saltatory conduction was absent because the axons had lost the insulating properties of the myelin sheath. The general approach used in these studies is important as it opens the way for selectively ablating individual lipids in complex membrane structures other than myelin and opens a new way for understanding the interactions of lipids with key membrane molecules (such as receptors, channels and transporters) in cells of the nervous system and elsewhere. References 1.

Betz H, Schefler R (Eds): Signalling mechanisms. Curt Opin Neurobiol 1997, 7:30?-429.

2.

Emr SD, Malhotra V (Eds): Membranes and sorting. Curt Opin Cell Biol 1997, 9:475-542.