Perspectives on developmental neurobiology最新文献

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.

The searching growth cone simultaneously processes multiple guidance cues and converts them into intracellular signals regulating axon extension, steering and eventually synapse formation. This overlap of signaling pathways ensures functional connectivity of the nervous system during development. While this complicates the genetic analysis of these signaling pathways, combination of genetic techniques available in Drosophila has begun to successfully address the role of some key signaling molecules during axon guidance.

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.

The monkey's foveola normally contains significant numbers of retinal ganglion cells. The somata of foveola cells are larger than those of other cells in the central retina. Their dendritic fields are up to 50 times larger in area than those of nearby cells in the foveal slope. Experimentally induced reductions in the number of ganglion cells in central retina results in alterations in the size and distribution of cells within the foveola. In these animals the foveola is abnormally small and contains an abnormally large number of cells having smaller than normal cell bodies and dendritic fields. These studies indicate that the formation of the foveola as well as the development of the morphology of cells within the foveola and foveal slope depend during development on high densities of retinal ganglion cells within the central retina.

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.

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.

Establishing molecular mechanisms of axon guidance presents one of the greatest challenges in understanding the development of the nervous system. There are many neurons, and each neuron by virtue of its location, biochemistry, and time of development, may generate a unique axon morphology in its response to environmental cues that may also change during development. The context dependence and combinatorial nature of these interactions make analysis of axon guidance particularly difficult. This article will focus on the neuronal growth cone as axon guidance is controlled by interaction of the growth cone with its environment. I present here an overview of growth cone motility from the perspective of cytoskeletal dynamics. I conclude with a discussion of our application of regional laser inactivation of growth cone proteins to address what proteins might be involved in locally modulating the cytoskeleton and how they affect growth cone motility.

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.

Vertebrate neurogenesis involves many distinct differentiation stages that are regulated by extrinsic signals. Survival and differentiation effects on cultured neurons of several lineages are elicited by members of the neurokine family of growth factors, ciliary neurotrophic factor (CNTF) and the related avian factor, growth promoting activity (GPA). The selective actions of these factors are mediated through the activation of heteromeric receptor complexes and depend on the presence of the ligand-binding receptor subunits CNTFR alpha and GPAR alpha. The in vivo localization of CNTFR alpha and GPAR alpha is consistent with the previously assigned biological functions but also suggest novel functions for these receptors and their ligands during neurogenesis.

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 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.