Bone morphogenetic protein signalling and vertebrate nervous system development

Transforming growth factor-beta (TGFbeta) signalling, particularly signalling from the bone morphogenetic protein (BMP) members of this protein family, is crucial for the development of both the central and peripheral nervous systems in vertebrates. Experimental embryology and genetics performed in a range of organisms are providing insights into how BMPs establish the neural tissue and control the types and numbers of neurons formed. These studies also highlight the interactions between different developmental signals that are necessary to form a functional nervous system. The challenges ahead will be to uncover functions of TGFbeta signalling in later stages of CNS development, as well as to determine possible associations with neurological diseases.     

Expression of glycoconjugates during development of the vertebrate nervous system

There is increasing evidence that carbohydrate antigens act as cell recognition molecules in the highly organized structure of the nervous system. These carbohydrate antigens may be expressed as glycolipids, glycoproteins or proteoglycans, and in some cases all three forms of these glycoconjugates, expressing identical carbohydrate epitopes, can be detected in a specific brain region. This article summarizes recent studies concerning the expression of glycoconjugates during development of the vertebrate central nervous system. These findings are discussed in association with current models of glycoconjugate function.     

Glycine-receptors in the vertebrate central nervous system

Evidence for the existence of glycine-receptors in the vertebrate central nervous system (CNS) has been reviewed and analyzed. Biochemical studies have supported iontophoretic findings that such receptors exist in several regions of the CNS. Subcellular studies on the displacement of 3H-strychnine binding by glycine and on the effects of strychnine on 3H-glycine binding have revealed that strychnine does not interact directly with glycine-receptors, lending support to studies performed in situ. Approaches toward glycine-receptors remain limited due to the inavailability of a specific glycine-antagonist.     

Plasticity and stem cells in the vertebrate nervous system

How and when do vertebrate neural precursor cells choose their fates? While some studies suggest a series of commitments on the road to fate choice, many recent experiments indicate that precursor fate choices can often be changed. Additionally, the identification of common gene control mechanisms in precursors suggest that these cells share fundamental properties throughout development.     

Axon guidance in the vertebrate central nervous system

The development of connections in the central nervous system depends on the ability of the tips of growing axons to find their appropriate, often distant, target field. Factors that regulate axon outgrowth may be distinct from those that influence direction finding. Tissue culture methods have helped to distinguish between possible in vivo mechanisms and, in some cases, have identified candidate molecules.     

Pattern formation in the vertebrate nervous system.

In recent years, the classical approaches of experimental embryology have been used in combination with more modern techniques to investigate aspects of neurogenesis. This combination has advanced our knowledge of several areas of neuronal development, including the lineages of neuronal precursors, the segmentation of the nervous system, and the patterning of the neural tube.     

Segmentation of the central nervous system in leech

Central nervous system (CNS) in leech comprises segmentally iterated progeny derived from five embryonic lineages (M, N, O, P and Q). Segmentation of the leech CNS is characterized by the formation of a series of transverse fissures that subdivide initially continuous columns of segmental founder cells in the N lineage into distinct ganglionic primordia. We have examined the relationship between the N lineage cells that separate to form the fissures and lateral ectodermal and mesodermal derivatives by differentially labeling cells with intracellular lineage tracers and antibodies. Although subsets of both lateral ectoderm and muscle fibers contact N lineage cells at or near the time of fissure formation, ablation experiments suggest that these contacts are not required for initiating fissure formation. It appears, therefore, that this aspect of segmentation occurs autonomously within the N lineage. To support this idea, we present evidence that fundamental differences exist between alternating ganglionic precursor cells (nf and ns primary blast cells) within the N lineage. Specifically, ablation of an nf primary blast cell sometimes resulted in the fusion of ipsilateral hemi-ganglia, while ablation of an ns primary blast cell often caused a 'slippage' of blast cells posterior to the lesion. Also, differences in cell behavior were observed in biochemically arrested nf and ns primary blast cells. Collectively, these results lead to a model of segmentation in the leech CNS that is based upon differences in cell adhesion and/or cell motility between the alternating nf and ns primary blast cells. We note that the segmentation processes described here occur well prior to the expression of the leech engrailed-class gene in the N lineage.     

Chordate origins of the vertebrate central nervous system.

Fine structural, computerized three-dimensional (3D) mapping of cell connectivity in the amphioxus nervous system and comparative molecular genetic studies of amphioxus and tunicates have provided recent insights into the phylogenetic origin of the vertebrate nervous system. The results suggest that several of the genetic mechanisms for establishing and patterning the vertebrate nervous system already operated in the ancestral chordate and that the nerve cord of the proximate invertebrate ancestor of the vertebrates included a diencephalon, midbrain, hindbrain, and spinal cord. In contrast, the telencephalon, a midbrain-hindbrain boundary region with organizer properties, and the definitive neural crest appear to be vertebrate innovations.     

Mechanisms of ventral patterning in the vertebrate nervous system

Dorsoventral patterning of the neural tube has a crucial role in shaping the functional organization of the CNS. It is well established that hedgehog signalling plays a key role in specifying ventral cell types throughout the neuroectoderm, and major progress has been made in elucidating how hedgehog signalling works in this ventral specification. In addition, other molecular pathways, including nodal, retinoic acid and fibroblast growth factor signalling, have been identified as important molecular cues for ventral patterning of the spinal cord, telencephalon and eye. Here, we discuss recent advances in this field, highlighting the emerging interplay of these signalling pathways in the molecular specification of ventral patterning at different rostrocaudal levels of the CNS.     

The phylogenic expression of plasmolipin in the vertebrate nervous system

Plasmolipin is a plasma membrane proteolipid is a major myelin membrane component (Cochary et al., 1990). In this study we report the phylogenic expression of plasmolipin in the vertebrate nervous system. Using Western blot analysis with polyclonal antibodies, we have analyzed membrane fractions, including myelin, from elasmobranchs, teleosts, amphibians, reptiles, birds and mammals. On the basis of immune detection, plasmolipin appears to be restricted to the mammalian nervous system. Comparison of the central and peripheral nervous systems of mammals showed only minor differences in the level of plasmolipin in these two regions. Within mammals, little quantitative differences were observed when rat, human and bovine membrane fractions were compared. The late evolutionary expression of plasmolipin which results in its restriction to mammals makes it unique among the (major) myelin proteins. The potential physiologic significance of these data are discussed.Abbreviations EDTA Ethylene diamine N.,NN tetracetic acid - EGTA Ethylene glycol bis-(B-Aminoethyl Ether) N,,NN tetracetic acid - MES ([N-Morpholino] ethane sulfonic acid) DCCD, N, Dicyclohexyl carbodiimide     

Development of trophic interactions in the vertebrate peripheral nervous system

During embryogenesis, the neurons of vertebrate sympathetic and sensory ganglia become dependent on neurotrophic factors, derived from their targets, for survival and maintenance of differentiated functions. Many of these interactions are mediated by the neurotrophins NGF, BDNF, and NT3 and the receptor tyrosine kinases encoded by genes of thetrk family. Both sympathetic and sensory neurons undergo developmental changes in their responsiveness to NGF, the first neurotrophin to be identified and characterized. Subpopulations of sensory neurons do not require NGF for survival, but respond instead to BDNF or NT3 with enhanced survival. In addition to their classic effects on neuron survival, neurotrophins influence the differentiation and proliferation of neural crest-derived neuronal precursors. In both sympathetic and sensory systems, production of neurotrophins by target cells and expression of neurotrophin receptors by neurons are correlated temporally and spatially with innervation patterns. In vitro, embryonic sympathetic neurons require exposure to environmental cues, such as basic FGF and retinoic acid to acquire neurotrophin-responsiveness; in contrast, embryonic sensory neurons acquire neurotrophin-responsiveness on schedule in the absence of these molecules.     

Developmental regulation of axon branching in the vertebrate nervous system

During nervous system development, axons generate branches to connect with multiple synaptic targets. As with axon growth and guidance, axon branching is tightly controlled in order to establish functional neural circuits, yet the mechanisms that regulate this important process are less well understood. Here, we review recent advances in the study of several common branching processes in the vertebrate nervous system. By focusing on each step in these processes we illustrate how different types of branching are regulated by extracellular cues and neural activity, and highlight some common principles that underlie the establishment of complex neural circuits in vertebrate development.     

Novel roles for collagens in wiring the vertebrate nervous system

Wiring the vertebrate nervous system is a multi-step process that relies heavily upon the role of transmembrane and extracellular adhesion molecules. Despite the extensive attention focused on such molecules, collagens, a large family of structural adhesion molecules expressed in the vertebrate nervous system, have been largely overlooked for roles in neural circuit formation. Recently, however, several studies have unexpectedly identified novel roles of collagens and collagen-like molecules in the developing vertebrate nervous system. Here, contributions of these collagens and collagen-like molecules in neural circuit formation are reviewed.     

Polysialic acid in the plasticity of the developing and adult vertebrate nervous system

Polysialic acid (PSA) is a cell-surface glycan with an enormous hydrated volume that serves to modulate the distance between cells. This regulation has direct effects on several cellular mechanisms that underlie the formation of the vertebrate nervous system, most conspicuously in the migration and differentiation of progenitor cells and the growth and targeting of axons. PSA is also involved in a number of plasticity-related responses in the adult CNS, including changes in circadian and hormonal patterns, adaptations to pain and stress, and aspects of learning and memory. The ability of PSA to increase the plasticity of neural cells is being exploited to improve the repair of adult CNS tissue.     

Lipofection of cDNAs in the embryonic vertebrate central nervous system.

Neurons from the embryonic brain of Xenopus were transfected in vivo with a vector expressing luciferase cDNA using a simple lipofection procedure. Luciferase activity was monitored quantitatively, and the protein was immunolocalized in whole-mount embryonic brains. Luciferase-expressing neurons were often intensely labeled, displaying a Golgi-like filling of their dendrites, axons, and growth cones. Luciferase expression could be targeted to the retina by simply removing the skin epidermis covering the area and exposing the whole embryo to the DNA-lipofectin mixture. Luciferase activity in transfected embryos rose to peak values during the first 48 hr posttransfection and was still detectable 28 days later. Cotransfection experiments in which embryonic nervous tissue was exposed simultaneously to two different genes, luciferase and chloramphenicol acetyl-transferase, showed that transfected cells coexpressed the two genes at an extremely high frequency (85%-100%). This offers the possibility of targeting functionally significant genes along with benign reporter genes in the developing CNS.     

ErbB receptors and the development of the nervous system

Tyrosine kinase receptors and their ligands allow communication between cells in the developing and adult organism. An extensive line of research has revealed that ‘neuregulins’, a family of EGF-like factors that signal via ErbB receptors, are used frequently for cell communication during nervous system development, and control a spectacular spectrum of developmental processes. For instance, during development of the peripheral nervous system, Schwann cells require neuronally-produced neuregulin (Nrg1) for growth, migration and myelination, neural crest cells rely on mesenchymally-generated Nrg1 signals for migration, while muscle requires neuronally-produced Nrg1 for the differentiation of a muscle spindle. In the central nervous system, neuregulin signals allow cells to act as guideposts or as barriers for axons during pathfinding. Neuregulin signals are also important in other organs, but the nervous system functions have received recently considerable attention due to the finding that particular haplotypes of Nrg1 and ErbB4 predispose to schizophrenia. Understanding the neuregulin signaling system can thus contribute to define causes of this devastating mental disorder.