Showing papers in "Perspectives on developmental neurobiology in 1996"

The NG2 chondroitin sulfate proteoglycan: a multifunctional proteoglycan associated with immature cells.

Abstract: In this review, we discuss the properties of the NG2 chondroitin sulfate proteoglycan, a structurally unique, integral membrane proteoglycan that is found on the surfaces of several different types of immature cells. NG2 is associated with multipotential glial precursor cells (O2A progenitor cells), chondroblasts of the developing cartilage, brain capillary endothelial cells, aortic smooth muscle cells, skeletal myoblasts and human melanoma cells. One common feature of these diverse cell types is that they retain the ability to divide throughout the life of the organism. The NG2 proteoglycan is a multifunctional protein; in vitro studies have shown that NG2 binds type VI collagen, interacts with and modulates the activity of the platelet-derived growth factor-alpha receptor, and inhibits neurite outgrowth. These functional properties are analogous to those of other proteoglycans such as syndecan, betaglycan, and neurocan, suggesting that structurally divergent proteoglycans can carry out similar functions within the organism.

Neurocan and phosphacan: two major nervous tissue-specific chondroitin sulfate proteoglycans.

Abstract: Neurocan is a multidomain hyaluronan-binding chondroitin sulfate proteoglycan that is synthesized by neurons, whereas the astroglial proteoglycan phosphacan is an mRNA splice variant representing the entire extracellular portion of a receptor-type protein tyrosine phosphatase. A glycoform of phosphocan (phosphocan-KS) that contains both chondroitin sulfate and keratan sulfate is present in the postnatal rat central nervous system (CNS). The concentration of neurocan in brain increases during late embryonic development but then declines steeply during the early postnatal period together with hyaluronan, and neurocan also undergoes extensive proteolytic processing during the course of brain development. In contrast, the concentrations of both phosphocan and phosphocan-KS rise steadily after embryonic day 20 to reach a plateau at about 2 weeks postnatally. In the embryonic CNS the distribution of neurocan mRNA is more widespread than that of phosphocan, which is primarily present in regions of active cell proliferation. Neurocan mRNA is also present in areas where the proteoglycan is not expressed, and there is evidence that the short open reading frame in its 5'-leader may function as a cis-acting regulatory signal for the modulation of neurocan expression in the developing CNS. Neurocan and phosphocan bind saturably, reversibly, and with high affinity to neural cell adhesion molecules (Ng-CAM/L1, NCAM, TAG-1/axonin-1) and to tenascin-C. The proteoglycans and their ligands have overlapping localizations in the CNS, and binding of phosphocan to Ng-CAM/L1, NCAM, and tenascin-C is mediated by complex-type N-linked oligosaccharides on the proteoglycan. Neurocan and phosphocan also bind to neurons and are potent inhibitors of neuronal and glial adhesion and neurite outgrowth. Through their interactions with neural cell adhesion and extracellular matrix molecules, these proteoglycans may play a major role in modulating cell adhesion, neurite growth, and signal transduction across the plasma membrane during the development of the CNS.

Functions of brain chondroitin sulfate proteoglycans during developments: interactions with adhesion molecules.

Abstract: Chondroitin sulfate proteoglycans (CSPGs), including neurocan and phosphocan, are believed to be major components of brain extracellular matrix that interact with other matrix proteins and cell surface receptors In addition, several brain CSPGs such as receptor protein tyrosine phosphatase beta are expressed as cell surface receptors that interact with proteins in the extracellular matrix and with receptors on neural cells Recent in vitro studies demonstrate that, although the brain CSPGs neurocan and phosphocan can promote transient adhesion of neuronal cells, they inhibit stable cell adhesion and neurite growth promoted by the cell adhesion molecule Ng-CAM/L1 Neurocan and phosphocan bind with high affinity to Ng-CAM/L1 and N-CAM which may be their major receptors on neurons These CSPGs also bind to other adhesion molecules, such as tenascin-C, and can differentially modulate adhesion of glia of tenascin-C Both the glycosaminoglycan and the core glycoproteins contribute to the function of the brain CSPGs When expressed in regions containing low levels of adhesion molecules, various CSPGs including phosphocan, neurocan, versican, aggrecan, and NG2 proteoglycan may act as barriers to cell migration and axonal growth In regions containing high levels of adhesion proteins, brain CSPGs may still act to maintain certain boundaries while allowing selective axonal extension to proceed There are numerous regions of overlap in the expression patterns of CSPGs and adhesion molecules in vivo, and the relative levels of these molecules as well as the organization of the extracellular matrix may be important factors that regulate the rate of axonal growth locally Differential expression of CSPGs may be important for modulating cell adhesion as well as axonal growth and guidance during neural development, and continued expression may prevent these processes in the normal nature nervous system as well as following brain injury

Microglia in human retina: a heterogeneous population with distinct ontogenies.

Abstract: Microglia of the adult human retina are a heterogeneous population of cells, some having characteristics of dendritic antigen presenting cells (DC) and others resembling macrophages, or MPS cells. Studies of the development of microglial distributions in human retina suggest that cells bearing macrophage markers are ontogenetically distinct from microglia that do not. Quantitative studies indicate that macrophage antigen immunoreactive microglia are a subpopulation CD45- and MHC-immunoreactive microglia. While CD45 and MHC-I and -II immunoreactive microglia are seen in the retina prior to the arrival of the vasculature, significant numbers of macrophage-positive microglia only arrive along with the vascular precursors, at about 14 to 15 weeks of gestation. Microglia appear to enter the retina from the ciliary margin prior to vascularization but from both the optic disc and ciliary margin, postvascularization. Macrophage antigen positive microglia enter the retina mainly via the optic nerve head. It is argued that macrophage-antigen positive microglia become established in the retina as vessel associated (perivascular and paravascular) microglia and that the MHC-positive, but macrophage-antigen negative microglia (representing DC), become established as the parenchymal, ramified microglia of adult retina.

Changes in neuropeptide phenotype after axotomy of adult peripheral neurons and the role of leukemia inhibitory factor.

Abstract: Adult peripheral neurons undergo dramatic shifts in gene expression following axotomy that are collectively referred to as the cell body reaction. Changes in neuropeptide expression are a prominent feature of these axotomized neurons. For example, while sympathetic, sensory, and motor neurons do not normally express the neuropeptides galanin and vasoactive intestinal peptide, they begin to do so within days after axotomy. In contrast, the expression of other peptides, which these neurons normally express, such as neuropeptide Y in sympathetic neurons and substance P in sensory neurons, is decreased. Recent studies in sympathetic neurons have demonstrated that leukemia inhibitory factor plays an important role in triggering these changes in neuropeptide phenotype in adult neurons. Future studies will be directed at determining to what extent LIF triggers the many other changes in gene expression after sympathetic axotomy and whether this cytokine plays a similar role in sensory and motor neurons.

The cytoskeleton in nerve growth cone motility and axonal pathfinding.

Abstract: Axonal pathfinding occurs through detection of environmental cues by cytoskeletal machinery that is responsible for growth cone migration The cycle of filopodial and lamellipodial protrusion, adhesion, and generation of tensions to advance a growth cone result from concerted actions of ABPs to regulate actin filament polymerization, assembly into networks and bundles, and production of tension to move the growth cone and its contents The direction of neurite elongation is controlled by forward movement of microtubules in growth cones, which is pioneered by the advance of microtubules into P domain of the leading margin Actin filaments both promote and impede this advance of microtubules in several ways This cytoskeletal machinery is controlled by major signaling mechanisms To understand growth cone guidance we must reveal the spatial and temporal changes generated in [Ca++]i, phospholipids, and protein phosphorylation and dephosphorylation, and then identify the ABPs and MAPs that are their targets

Brevican: a major proteoglycan in adult brain.

Abstract: A diverse set of proteoglycans is expressed in the developing and adult brain. This is in stark contrast to the fact that most extracellular matrix components, including fibronectin, laminin, and collagens, are not expressed in adult brain parenchyma. This suggests that proteoglycans may play a major functional role in cell-cell and cell-matrix interactions in the brain. Brevican is a member of the aggrecan/versican family of proteoglycans, containing a hyaluronic acid-binding domain in its N-terminus and a lectin-like domain in its C-terminus. Brevican has the smallest core protein among this family and is one of the most abundant chondroitin sulfate proteoglycans in the adult brain. Expression of brevican is highly specific in the brain and increases as the brain develops. These observations suggest that brevican may play a role in maintaining the extracellular environment of mature brain as a major constituent of the adult brain extracellular matrix.

The glypican family of heparan sulfate proteoglycans: major cell-surface proteoglycans of the developing nervous system.

Abstract: The glypican family of glycosylphosphatidylinositol-anchored heparan sulfate proteoglycans comprises four vertebrate members, glypican, cerebroglycan, OCI-5, and K-glypican, and the Drosophila protein, daily. These molecules share highly conserved protein structural features that sharply distinguish them from the syndecans, the other major class of cell surface heparan sulfate proteoglycans. All members of the glypican family are expressed in the developing nervous system, with one member (cerebroglycan) being restricted to that tissue. In the developing rodent brain, glypican and cerebroglycan--which appear to be the most abundant family members in that tissue--are expressed mainly by neurons, and both are strongly localized to axons. In the case of cerebroglycan, expression is limited to axons at or about the time they are extending toward their targets. Although the functions of the vertebrate members of this family are not known, in Drosophila, the effects of mutations in the daily gene suggest a role for members of the glypican family in regulating cell cycle progression during the transition of neural cells from proliferation to neuronal differentiation. It is likely that proteoglycans of the glypican family also play other important roles in neural development.

Calcium and Free Radicals: Mediators of neurotrophic factor and excitatory transmitter-regulated developmental plasticity and cell death.

Abstract: An intricate interplay between neurotrophic factor and excitatory transmitter signaling systems exists in both the developing and adult brain. Interactions between these signaling systems appears to be a fundamental mechanism regulating adaptive neuritic pruning and cell death. Accordingly, genetically and environmentally induced imbalances in this regulatory system are implicated in the pathogenesis of a variety of acute (such as stroke and traumatic brain injury) and chronic (such as Alzheimer's and Parkinson's diseases) neurodegenerative disorders. Neurons exhibit both acute and delayed responses to neurotrophic factors and excitatory transmitters; acute responses include rapid structural remodeling of growth cones and synaptic contacts, and delayed responses include induction or suppression of the expression of gene products involved in neuroprotection. Intracellular free Ca2+ and free radicals appear to play key roles as mediators of both acute and delayed responses of neurons to excitatory transmitters and neurotrophic factors. For example, the delayed response to bFGF includes stabilization of Ca2+ homeostasis and induction of antioxidant enzymes; both of these actions of bFGF antagonize the dendrite outgrowth-stabilizing and excitotoxic actions of glutamate. Intricate regulatory interactions exist between glutamate and neurotrophic factor signaling systems so that glutamate can induce the expression of neurotrophic factors and their receptors, and neurotrophic factors modulate the expression of exitatory transmitter receptors. A novel signaling system that can interact with both glutamate and neurotrophic factor systems is that of the beta-amyloid precursor protein, which appears to play important roles in neuronal plasticity and survival. A working model for the regulation of neuronal survival and connectivity is presented, which considers spatial and temporal constraints on release of, and receptors for, neurotrophic factors and excitatory transmitters.

Microtubule-associated proteins, phosphorylation gradients, and the establishment of neuronal polarity.

Abstract: Axonogenesis is the earliest step in acquisition of neuronal polarity. The subcellular mechanisms underlying this pivotal event are unknown. Because of the abundant presence and functional necessity of microtubule-associated proteins in growing neurites, a large effort has been directed at characterizing their role in establishment and maintenance of neuronal polarity. One unsolved puzzle is how MAPs, most of which are unpolarized in early stages of development, can locally influence microdifferentiation of axons and dendrites. In this review, we discuss recent evidence suggesting that locally controlled phosphorylation of microtubule-associated proteins tau and MAP1B may play a role in establishment of polarity and early axonal outgrowth.

Selective neural cell adhesion molecule signaling by Src family tyrosine kinases and tyrosine phosphatases.

Abstract: Nerve growth cone guidance is a highly complex feat, involving coordination of cell adhesion molecules, trophic factor gradients, and extracellular matrix proteins. While navigating through the developing nervous system, the growth cone must integrate diverse environmental signals into a singular response. The repertoire of growth cone responses to these extracellular cues includes axonal growth, fasciculation, and synaptic stabilization, which are achieved through dynamic changes in the cytoskeleton and modulation of gene expression. It has become evident that interactions between cell adhesion molecules can activate intracellular signaling pathways in neurons. Such signaling pathways are just beginning to be defined for the axonal growth promoting molecules L1 and NCAM which are members of the immunoglobulin (Ig) superfamily. Recent findings have revealed that L1 and NCAM induce neurite outgrowth by activating intracellular signaling pathways in the growth cone mediated by two different members of the src family of nonreceptor protein tyrosine kinases (PTKs), pp60(c-src) and p59(fyn5,6). Growth cones display diverse morphologies and variable motility on these different cell adhesion molecules, which are likely to be generated by src kinases. In this review we will address novel features of nonreceptor PTKs of the src family which dictate their distinctive molecular interactions with cell adhesion molecules and signaling components.

Small GTPases in axon outgrowth.

Abstract: We propose that small GTPases in the Rho/Rac/Cdc42 subfamily play a central role in signaling pathways from cell surface receptors to actin cytoskeleton changes in the growth cone. The proposal is based upon the following evidence. First, the Rho/Rac/Cdc42 subfamily GTPases have been shown to regulate various aspects of cytoskeletal organization from budding yeast to mammalian fibroblasts. Second, perturbation of GTPase activities of Rac and Cdc42 in neurons by constitutively active and dominant negative mutants results in specific defects in axon and dendrite outgrowth. In addition to reviewing existing experimental evidence, we will discuss the implications of such a model and the potential relationship with other signaling pathways.

Agrin: an extracellular matrix heparan sulfate proteoglycan involved in cell interactions and synaptogenesis

Abstract: Recent studies have documented important roles for heparan sulfate proteoglycans in the control of nervous system development. Agrin is an extracellular matrix protein identified and named based on its involvement in the aggregation of acetylcholine receptors (AChRs) during synaptogenesis at the neuromuscular junction. Recent studies have demonstrated that agrin is a large extracellular heparan sulfate proteoglycan, with a molecular mass in excess of 500 kDa and a protein core of 220 kDa. Emerging evidence indicates that agrin's function is not limited to its role in AChR aggregation during synaptogenesis, as the majority of agrin expression occurs in the developing central nervous system, especially in developing axonal tracts. This review examines recent studies suggesting a role for agrin in the regulation of cell-cell interactions, most notably by its ability to interact with the neural cell adhesion molecule. In addition, other potential roles for the heparan sulfate chains of agrin during nervous system development are explored.

Spatiotemporal gradients of cell genesis in the primate retina.

Abstract: A cardinal event in the development of all brain structures is the time at which progenitor cells leave the cell cycle and begin to differentiate. We examined cell genesis in the retina of the macaque monkey (Macaca mulatta) by labeling dividing cells with radioactive thymidine ([3H]TdR) and following their fate at terminal division by virtue of their remaining radiolabeled after a long survival period. A number of distinct patterns of cell genesis were observed. The two tissues generated by the optic vesicle, the retinal pigment epithelium and neuroretina, share closely coincident temporal and spatial patterns of cell genesis, indicating that this process may be controlled by a common mechanism. Although overlapping to varying degrees, a clear sequence of genesis was revealed between specific cell types within the neuroretina: ganglion cells are generated first, followed by horizontal cells, cone photoreceptors, amacrine cells, Muller cells, bipolar cells, and, finally, rod photoreceptors. Retinal ganglion cells of differing soma diameter are born at different times-the smallest cells are generated early, the largest late, suggesting a further refined sequence of the functional classes of monkey retinal ganglion cells (first P gamma, then P beta, last P alpha). In addition, at sites where a homogeneous population of cells are crowded and stacked on top of each other (the foveola and perifovea for cones and ganglion cells, respectively) there is a vitreal-to-scleral intralaminar pattern of [3H]TdR labeled cell placement, which reflects both time of genesis and pattern of movement during foveation. These gradients suggest several scenarios for cell fate specification in the retina, many of which might not be obvious in mammals that develop more quickly and have less specialized retinal structure. Thus, data from the highly specialized and slowly developing macaque retina can help to understand visual development in humans and indicate useful avenues for future experimental studies in other species.

Shared cell adhesion molecule (CAM) homology domains point to CAMs signalling via FGF receptors.

Abstract: A number of cell adhesion molecules (CAMs) promote neurite outgrowth following transfection and expression in a variety of monolayer cells. We have shown that N-cadherin, L1 and some isoforms of NCAM can stimulate neurite outgrowth from PC12 cells and primary neurons following transfection and expression at physiologically relevant levels in NIH-3T3 cells. A number of observations suggest that these CAMs stimulate neurite outgrowth by activating a convergent second messenger pathway in neurons rather than by modulating adhesion per se, and that an early or initial step in the pathway involves activation of a tyrosine kinase. The observation that the fibroblast growth factor receptor (FGFR) contains an evolutionarily conserved sequence with homology to the above CAMs (the CAM homology domain-CHD) points to the possibility that CAMs might interact with, and signal via, FGFR tyrosine kinases. This hypothesis has been substantiated by a number of independent experimental tests. We present a speculative model in which the evolutionary conservation of a pair of complementary binding motifs can account for a direct binding interaction between FGFR and the above three CAMs.

Calcium and chemotropic turning of nerve growth cones.

Abstract: Cultured Xenopus spinal neurons exhibit chemotropic turning toward the source of neurotransmitters acetylcholine and glutamate. Here we review the experimental evidence that transmitter-induced turning of the growth cone is mediated by an influx of Ca2+, that a gradient of intracellular Ca2+ within the growth cone is responsible for the directional growth cone response, and that asymmetric filopodia formation precedes and is essential for the turning response.

Prevention of neuronal apoptotic death by neurotrophic agents and ganglioside GM1: insights and speculations regarding a common mechanism.

Abstract: The purpose of this article is to present the concept that the capacity of ganglioside GM1 to promote neuronal survival, and probably other differentiative and neuroprotective actions, is dependent on activation of neurotrophic factor receptor tyrosine kinases. Exogenously supplied ganglioside GM1 mimics or potentiates many activities of neurotrophic factors, including maintenance of survival, stimulation of neurite outgrowth, and protection from excitotoxic and neurotoxic insults. The mechanism of such actions has been largely unknown. We have found that GM1 will rescue cultured sympathetic neurons and PC12 (pheochromocytoma) cells from apoptotic death induced by withdrawal of nerve growth factor (NGF) or serum and have exploited these model systems to study the ganglioside mechanism of action. We have found evidence that part of the survival-promoting activity of GM1 is dependent on the presence, dimerization, and activation of the Trk NGF receptor tyrosine kinase and that GM1 causes a detectable increase in Trk receptor autophosphorylation. We postulate that exogenously supplied GM1 causes increased ligand-independent dimerization of Trk molecules within membranes, thereby leading to its activation and promotion of survival. We further speculate that GM1 may have similar effects on other receptor tyrosine kinases and that such actions could account for its mimicry and potentiation of neurotrophic factors in vitro as well as in vivo.

N-syndecan: structure and function of a transmembrane heparan sulfate proteoglycan.

Abstract: N-syndecan is a member of the syndecan family of transmembrane heparan sulfate proteoglycans that was cloned initially from neonatal rat Schwann cells and is the principal syndecan expressed during early postnatal development in the central and peripheral nervous systems. Purified N-syndecan binds in vitro with high affinity to several extracellular regulatory ligands, including basic fibroblast growth factor, the secreted adhesive protein heparin binding growth-associated molecule, and a novel collagen-like protein secreted by Schwann cells. These extracellular ligands utilize the heparan sulfate chains of N-syndecan for binding. Based on the striking amino acid sequence homology of the cytoplasmic domain of N-syndecan to syndecan-1, it is proposed that N-syndecan associates with the actin-based cytoskeleton. N-syndecan core proteins self associate by means of an unusual dimerization motif comprised of the transmembrane domain and a short flanking sequence in the ectodomain. Similar to other single transmembrane domain receptor proteins, it is suggested that ligand-regulated dimerization of N-syndecan represents a mechanism for regulating downstream signaling activities. In rat brain tissue a significant fraction of the N-syndecan molecules are present in a soluble form, presumably as a result of proteolytic membrane shedding. A model is presented for morphoregulatory activity of N-syndecan in which extracellular ligand-induced clustering of N-syndecan molecules on the cell surface promotes cytoskeletal association and reorganization. Membrane shedding separates the functional domains of the proteoglycan and terminates this activity.

Regulation of oligodendrocyte cell survival and differentiation by ciliary neurotrophic factor, leukemia inhibitory factor, oncostatin M, and interleukin-6

Abstract: The regulation and maintenance of developmental lineages by trophic factors, both cell-mediated and soluble, is a key aspect of cellular differentiation in the nervous system. In this review we focus on oligodendrocytes and their progenitors and how differentiation and survival are regulated by four neuropoietic cytokines: ciliary neurotrophic factor, leukemia inhibitory factor, oncostatin M, and interleukin-6 (IL-6). We discuss how these cytokines act as "broad spectrum" factors. That is, how, even within a specific cell lineage, a given cytokine may have different effects on the target cells at various stages of differentiation.

Functional compartmentalization of the neuronal growth cone: determining calcium's place in signaling cascades.

Abstract: The growth cone is generally regarded as the basic unit of neuronal organization concerned with development of connections within the nervous system. The discussion below illustrates that the growth cone itself can be subdivided into distinct units of organization. It is this functional compartmentalization which enables the growth cone to read the molecular terrain it traverses and to convert this information into precise motor events. Our discussion will focus on the flow of information from the environment to the growth cone. In particular, we will follow signaling events from their remote processing within filopodia to the biological equivalent of a central processing unit in the core of the growth cone.

On the track of cell survival pharmaceuticals in the oligodendrocyte type-2 astrocyte lineage.

Abstract: The identification of compounds that can protect cells against death induced by exposure to noxious stimuli and against programmed cell death (apoptosis) associated with exposure to inadequate amounts of trophic factors is of great interest in contemporary biology. We have found that N-acetyl-L-cysteine (NAC) is able to promote cell survival in these two distinct experimental paradigms of, respectively, "death by murder" and "death by neglect." In the former case, NAC prevented the death of oligodendrocytes induced by glutamate or tumor necrosis factor-alpha (TNF-alpha), and also prevented TNF-alpha-induced death of L929 cells. NAC also acted in synergy with ciliary neurotrophic factor (CNTF) to prevent killing of oligodendrocytes by TNF-alpha. In analysis of "death by neglect," NAC markedly enhanced the extent of spinal ganglion neuron survival obtained with suboptimal concentrations of nerve growth factor and of oligodendrocyte survival obtained with suboptimal concentrations of CNTF or insulin-like growth factor-1. Surprisingly, significant rescue of oligodendrocytes from apoptosis was also observed with combinations of NAC with progesterone, vitamin C, or Trolox, a water-soluble vitamin E analogue, although not with any of these compounds applied individually. These results demonstrate that cocktails of small molecules such as those we have studied may have beneficial effects not predictable from the action of any individual member of the cocktail. In light of the long clinical history of therapeutic use of NAC and the other compounds identified in our studies, we suggest that it may be of interest to examine use of NAC alone, or combinations of NAC with the other small molecules we have studied, in conditions in which certain toxin-mediated forms of cell death or apoptosis contribute significantly to disease.

Synaptic development in macaque monkey retina and its implications for other developmental sequences.

Abstract: New and existing data are presented regarding synaptic development in primate retina with the aims to identify the sequence in which individual cell types form synapses in the inner plexiform (IPL) and outer plexiform (OPL) layers; to compare synaptic development sequences in cone-dominated fovea and rod-dominated peripheral retina; to compare synaptic formation with other aspects of cell differentiation; and to explore the possible roles for synapses in development The first synapses are formed in the foveal IPL by bipolar axons at fetal day 55, followed at fetal day 60 by cone ribbon synapses Amacrine synapses in the foveal IPL only appear in significant numbers at fetal day 88 In peripheral retina amacrine synapses are formed at fetal day 78, bipolar at 99, and photoreceptors at 105 Thus, the fovea forms the first synapses and the IPL matures before the OPL across the retina, but the fovea has a different bipolar/amacrine sequence than peripheral retina Foveal synapses are present before many photoreceptor-specific proteins such as opsins can be detected, suggesting that some phenotypic information from the inner retina could influence the direction of photoreceptor development The early synaptic development in the fovea may serve an important mechanical role during subsequent cell migrations that form the mature foveal pit and tightly packed cone foveola

Signal transduction pathways activated by ciliary neurotrophic factor and related cytokines.

Abstract: Neuropoietic cytokines such as ciliary neurotrophic factor, leukemia inhibitory factor, and interleukin-6 are known to be responsible for a wide variety of effects on cells of the immune and nervous systems. The mechanisms by which such diverse effects are regulated and coordinated within cells is of central importance to the understanding of how these molecules function during development. This review discusses the receptor complexes through which neuropoietic cytokines signal and the mechanisms by which activation of specific enzymes such as the Jak family of kinases are transduced into changes of gene expression through molecules such as the Stat proteins. This review also discusses how this JAK-Stat signaling pathway is thought to interact with other known cascades, such as the mitogen-activated protein kinase pathway.

GAP-43: putting constraints on neuronal plasticity.

Abstract: The brain must balance the need for synaptic precision with the ability to generate and change connectivity patterns in response to environmental stimuli. GAP-43 is a phosphoprotein associated with the cytosolic surface of the membrane, and is one of the most abundant among the small subset of total cellular proteins transported to the growth cone. It appears to play an unusual role amplifying signals from the microenvironment. One of the several ways to perform this task involves interaction of GAP-43 with the G protein transduction cascade. In mice rendered GAP-43 null by homologous recombination, some nerves manifest aberrant growth at decision points, such as the optic chiasm. Thus, GAP-43 may work via modulation of signaling cascades, rather than autonomously causing growth, and could serve to keep plasticity within constraints needed to generate and maintain accurate synaptic wiring.

Tyrosine phosphorylation and protrusive structures of the growth cone.

Abstract: Protein-tyrosine kinase, such as those of the trk and Eph families, serve as membrane receptors for extracellular cues which regulate the rate and direction of growth of numerous groups of axons. Certain cytoplasmic protein-tyrosine kinases, such as src, are also abundant in growth cones. But, how protein-tyrosine phosphorylation regulates the growth cone is poorly understood. We discuss here potential roles for tyrosine phosphorylation in the protrusive structures of the growth cone, especially filopodia, which are important in detecting cues. A particular focus is the integrin receptor for substrate-bound growth promoters like laminin. Changes in tyrosine phosphorylation may be important in both facilitating and mediating the interaction of filopodia with these growth promoters.

Investigations of signaling pathways in axon growth and guidance.

Abstract: The retinotectal projection in chick is a well studied model system for axon guidance. The 'stripe assay' provides a unique tool for investigating underlying molecules and mechanisms of axon guidance by non-diffusible substrate bound molecules in vitro. By combining this assay with a modified 'Campenot chamber', we have now investigated the role of several second messenger systems in this type of axon guidance by confronting growing axons with various drugs that are known to influence intracellular signaling. We have shown that extracellular, and most probably intracellular Ca++ is not required for this type of axon guidance, which also rules out the need for Ca++-dependent adhesion molecules like cadherins. While at least calmodulin and protein kinase C seem to be involved in axon elongation, inhibiting their function did not alter the growth cones' choice. Inhibition of other kinases, G-proteins and signaling components also failed to influence this guidance. These results may indicate that parallel signaling pathways take part in the molecular mechanism of this type of axon guidance.

Development of photoreceptor mosaics in the primate retina.

Abstract: The mosaic of rods and cones in the primate retina is the neuronal array where the visual world is first mapped onto the central nervous system. Rods, which mediate scotopic vision, and cones, which mediate photopic and color vision, are found in all vertebrate species. However, regional differences in the topographic arrangement and ratio of rods to cones vary dramatically among species, including different primates. Furthermore, the proportion and distribution of the wavelength-sensitive cone subtypes vary considerably between primates that occupy different visual habitats. What genetic or environmentally regulated mechanisms specify the position, phenotype, and ratios of photoreceptor subtypes? Available data suggest that the transient appearance of early-differentiating cones may serve to delineate basic species-specific retinal coordinates and determine the opsin phenotype of local assemblies of cones in the fetal photoreceptor mosaic. This article will summarize presently available data and our ideas of how the photoreceptor mosaic is organized in the adult primate retina, the features of these mosaics, which vary between primate species, and the developmental mechanisms, which may account for the emergence of photoreceptor position and specification of their phenotypes in the primate retina.

Genetic control of neural cell apoptosis.

Abstract: Apoptosis is a mode of cell death in which the cell plays an active role in its own death. Apoptosis occurs both within and outside the nervous system. Neural apoptosis occurs not only in neural development, but also in pathophysiological states such as stroke and beta-amyloid peptide toxicity. The mechanism by which apoptosis occurs is unknown, but several genes controlling the process have been identified. In some cases, these genes also have an effect on necrotic neural cell death. The finding that the cell plays an active role in its own death, and that specific gene products are involved, suggests that therapeutic intervention may be feasible.

Leukemia inhibitory factor and ciliary neurotrophic factor in sensory neuron development.

Abstract: Leukemia inhibitory factor (LIF),-ciliary neurotrophic factor (CNTF), and related proteins are potentially involved in several aspects of sensory neuron development. There is evidence that LIF promotes the differentiation of sensory neurons from progenitor cells of neural crest origin. Later in development, LIF, CNTF, oncostatin M and interleukin-6 promote the survival of cultured neurons. Some neurons, like those of the nodose ganglion, respond early in their de development to these factors, whereas other neurons, like those of the trigeminal ganglion, respond much later. In addition to promoting sensory neuron survival, there is some evidence that LIF is able to influence neurotransmitter and neuropeptide expression in these neurons. These observations suggest that several kinds of sensory neurons may be influenced in various ways by LIF and related factors at different stages of their development.

SV2proteoglycan: a potential synaptic vesicle transporter and nerve terminal extracellular matrix receptor.

Abstract: SV2Proteoglycan (SV2pg) is a specific component of small clear synaptic vesicles. It is a keratan sulfate proteoglycan with oligosaccharide side chains N-linked to a core protein of 80 kDa. Two glycosylated forms, H and L, are present in synaptic vesicles. The amino acid sequence suggests that SV2pg contains 12 transmembrane domains and is homologous to bacterial and eukaryotic sugar transporters. Although its structure suggests that SV2pg is a vesicular transporter, what it transports is unknown. SV2pg is probably not a neurotransmitter transporter, since that function resides in an unrelated family of synaptic vesicle proteins. In addition to its vesicular function, SV2pg may have a secondary function as an extracellular matrix (ECM) receptor on the nerve terminal surface. At the electric organ synapse, which is closely related to the neuromuscular junction. SV2pg is bound to laminin, a component of the synaptic ECM. SV2pg is only associated with laminin on the nerve terminal surface, not in the synaptic vesicle. Studies on synaptogenesis during motor nerve regeneration have suggested that nerve terminal ECM receptors play an important role in synaptic recognition.