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In vitro changes of ganglioside immunostain localization in developing neural cells.

The immunostains of GD3, c-pathway polysialogangliosides and gangliotetraosylgangliosides belonging to the a- and b-pathways were analyzed in embryo optic lobe cells. Cells were cultured in serum free media with, and without, bovine brain ganglioside mixture (largely gangliotetraosylgangliosides). Control cells differentiated in vitro, whereas ganglioside treated cells emitted almost no neurites. In immature cells, GD3 and c-gangliosides were extensively expressed and their immunostains were observed all over the cell (general localization), whereas gangliotetraosylgangliosides were scanty and their stain was preferentially restricted to discrete areas (in clusters). In control differentiated cells, the GD3 expression was strikingly reduced and its immunostain appeared in clusters; c-gangliosides were abundant and their stain was found with general localization; the expression of gangliotetraosylgangliosides became important and their stain was observed with general localization in most of the positive cells. In ganglioside treated cells, in spite of their undifferentiated morphology, the gangliotetraosylganglioside stain appeared with general localization. These results suggest that gangliosides involved in neural ontogenesis are preferentially located in clusters when they are scarce and have general localization when they are abundant in membranes.

Animals↗

Role of neurotrophins in the control of neural development: neurotrophin-3 promotes both neuron differentiation and survival of cultured chick retinal cells.

The effects of neurotrophins brain-derived neurotrophic factor and neurotrophin-3 on cultured dissociated cells from chick retina were studied at several embryonic ages from day 4 to day 13. Precursor cells from days 4-7 retinas proliferated in vitro and, after 20 h in culture, a proportion of them underwent spontaneous differentiation, as judged by both [3H]thymidine uptake and acquisition of neuronal morphology and neuron-specific markers. Brain-derived neurotrophic factor did not affect neuronal differentiation, although this factor supports survival of differentiated retinal ganglion cells [Rodríguez-Tébar et al. (1989) Devl Biol. 136, 296-303]. However, in cultures from young undifferentiated retinas, neurotrophin-3 produced up to a 2.5-fold increase in the number of [3H]thymidine-positive neurons, i.e. those that in vitro replicated their DNA. Moreover, in older retinas, neurotrophin-3, like brain-derived neurotrophic factor, supported the survival of differentiated retinal ganglion cells over a short developmental period. This effect was negligible at embryonic day 5, maximal at day 9, decreased at day 11 and was absent at embryonic day 13. Neurotrophin-3 also supported the survival of a population of amacrine neurons. This effect was modest at embryonic day 9, and increased at days 11 and 13. Our results show that, whereas the action of brain-derived neurotrophic factor is restricted to differentiated neurons, neurotrophin-3 exerts two distinct successive actions on retinal cells in vitro: first, this factor promotes either differentiation of neuroepithelial cells or maturation of recently differentiated neurons, and later in development, this factor supports the survival of differentiated retinal ganglion and amacrine cells but only during a discrete post-differentiation period.

Animals↗

Cellular transglutaminases in neural development.

Enzymes of the transglutaminase family catalyze the Ca(2+)-dependent covalent cross-linking of peptide-bound glutamine residues of proteins and glycoproteins to the epsilon-amino group of lysine residues to create inter- or intramolecular isopeptide bonds. Transglutaminases can also covalently link a variety of primary amines to peptide-bound glutamine residues giving rise to two possibilities; firstly, where the primary amine has two or more amino groups, further catalysis can result in the formation of cross-linked bridges between glutamine residues, and secondly, where the primary amine is a monoamine, glutamine residues are rendered inert to further modification. The products are therefore in the main, homo- or heterodimers, or extensive, metabolically-stable multimeric complexes or matrices. Ca(2+)-dependent transglutaminase activity is present in the mammalian peripheral and central nervous systems and transglutaminase-catalyzed cross-linking of endogenous substrates has been demonstrated in neurons of Aplysia and the mammalian brain. Transglutaminase activity increases in the brain during development, principally owing to the increasing preponderance of glial cell activity. In a few regions including the cerebellar cortex, activity is also high in early development. Cellular transglutaminases occur widely in differentiating cells and tissues in mammals, with more than one transglutaminase frequently associated with a single cell type. The primary protein sequences of three cellular transglutaminases have been fully determined in different species, together with that of a mammalian protein homologue (band 4.2) which shares extensive sequence homologies with transglutaminases, but lacks the active site cysteine residue. The upstream sequences of two mammalian cellular transglutaminase genes (C and K) contain numerous regulatory sites, and an invertebrate transglutaminase, annulin, is spatially regulated within homeodomains. Multiple molecular forms of transglutaminase C and possibly other cellular transglutaminases exist in mammalian brain. The emerging picture is one of a family of cytosolic and membrane-bound proteins central to several regulatory pathways whose functions is to stabilize the cellular and intercellular superstructure in growing organisms. The targeted formation of glu-lys isopeptide bonds between proteins is central to this function. Cytoskeletal proteins, membrane-associated receptors, enzymes in signal transduction pathways and extracellular glycoproteins are candidate substrates as are polyamines, but few cellular proteins have been identified as components of naturally-occurring covalently-bonded matrices. Transglutaminases participate in the programme of neuronal differentiation in some but not all classes of neurone. Both neuronal and non-neuronal expression of transglutaminases may be important for guidance of migrating neurons or growth cones and sustainment of cell shape and coordinates during development.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗

Zebrafish embryology and neural development.

The zebrafish is rapidly increasing in popularity with developmental biologists. Driving this interest are the elegant methods for in vivo observations and recovery of early developmental mutations. The past year has seen the introduction of additional methods for in vivo manipulation of identified cells and the application of these methods to mutant analysis.

Animals↗

Mechanisms of estrogen action during neural development: mediation by interactions with the neurotrophins and their receptors?

Estrogen enhances the growth and differentiation of neurites within the developing forebrain. A critical issue is whether these developmental actions of estrogen are mediated directly or indirectly by means of autocrine responses or local paracrine mechanisms, through interactions with growth factors, such as the neurotrophins, and their receptors. Support for the latter hypothesis comes from our recent observations of co-expression of estrogen receptor mRNA with the mRNAs for the neurotrophins and their receptors; differential and reciprocal up-regulation of estrogen and NGF receptor mRNA and protein expression by estrogen in adult female rat sensory neurons, PC12 cells; and cerebral cortical cultures; and putative estrogen response elements in the NGF, BDNF, trkA and p75 genes. Estrogen and the neurotrophins may influence each other's actions by regulating receptor and ligand availability or by reciprocal regulation at the level of signal transduction or gene transcription. The neurotrophins may serve as regulatory "switches" for the apparent developmentally-regulated, differential pattern of estrogen receptor regulation by its ligand, whereby their ability to increase estrogen receptor levels significantly may be sufficient to override the intrinsic suppressive action of estrogen on its receptor. Estrogen and the neurotrophins, acting in concert and reciprocally, may stimulate the synthesis of proteins required for neuronal differentiation, survival and maintenance of function.

Adult↗

Eph/ephrin signaling in morphogenesis, neural development and plasticity.

Ephrins are cell-surface-tethered ligands for Eph receptors, the largest family of receptor tyrosine kinases. During development, the Eph/ephrin cell communication system appears to influence cell behavior such as attraction/repulsion, adhesion/de-adhesion and migration, thereby influencing cell fate, morphogenesis and organogenesis. During adulthood, the Eph/ephrin system continues to play roles in tissue plasticity, for example in shaping dendritic spines during neuronal plasticity. Mechanistically, Eph-ephrin repulsive behavior appears to require ligand-receptor internalization and signaling to Rho GTPases.

Animals↗

Chondroitin sulfate proteoglycans in neural development and regeneration.

Proteoglycans are of two main types, chondroitin sulfate (CSPGs) and heparin sulfate (HSPGs). The CSPGs act mainly as barrier-forming molecules, whereas the HSPGs stabilise the interactions of receptors and ligands. During development CSPGs pattern cell migration, axon growth pathways and axon terminations. Later in development and in adulthood CSPGs associate with some classes of neuron and control plasticity. After damage to the nervous system, CSPGs are the major axon growth inhibitory component of the glial scar tissue that blocks successful regeneration. CSPGs have a variety of roles in the nervous system, including binding to molecules and blocking their action, presenting molecules to cells and axons, localising active molecules to particular sites and presenting growth factors to their receptors.

Animals↗

p63 is an essential proapoptotic protein during neural development.

The p53 family member p63 is required for nonneural development, but has no known role in the nervous system. Here, we define an essential proapoptotic role for p63 during naturally occurring neuronal death. Sympathetic neurons express full-length TAp63 during the developmental death period, and TAp63 levels increase following NGF withdrawal. Overexpression of TAp63 causes neuronal apoptosis in the presence of NGF, while cultured p63-/- neurons are resistant to apoptosis following NGF withdrawal. TAp63 is also essential in vivo, since embryonic p63-/- mice display a deficit in naturally occurring sympathetic neuron death. While both TAp63 and p53 induce similar apoptotic signaling proteins and require BAX expression and function for their effects, TAp63 induces neuronal death in the absence of p53, but p53 requires coincident p63 expression for its proapoptotic actions. Thus, p63 is essential for developmental neuronal death, likely functioning both on its own, and as an obligate proapoptotic partner for p53.

Aging↗

Transient alterations in neurotransmitter levels during a critical period of neural development in coho salmon (Oncorhyncus kisutch).

The time of parr-smolt transformation (PST) in salmon is a critical period of brain development during which the olfactory imprinting on the natal stream takes place. PST is associated with a surge of plasma thyroxine. We report here similar surges in the brain content of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA), norepinephrine (NE), and glutamine (Gln). Other putative neurotransmitters, such as glutamate and aspartate show no such change while gamma-amino-butyric acid (GABA) shows a minor elevation.

Animals↗