Perspectives on developmental neurobiology最新文献

The sympathetic neurons that innervate eccrine sweat glands undergo a phenotypic switch from noradrenergic to cholinergic and peptidergic. The changes in neurotransmitter choice are retrogradely specified by interactions with the target tissue that are mediated by a secreted differentiation factor. Production of the target-derived differentiation factor requires noradrenergic innervation. The switch from noradrenergic to cholinergic and peptidergic is reproduced in culture when neonatal sympathetic neurons are treated with members of the neuropoietic cytokine family, leukemia inhibitory factor (LIF) or ciliary neurotrophic factor (CNTF), suggesting that these cytokines might be responsible for the target-induced change in neurotransmitter properties. Analysis of transgenic mice that lack either LIF or CNTF or both, however, does not support their candidacy: the transmitter properties of the sweat gland innervation is indistinguishable from that of wild-type mice. It seems likely that another and novel member of the, family is responsible.

Two major hypotheses concerning programmed cell death are that it is the end result of a gene expression pathway and that it is the cellular response to conflicting growth control signals. These ideas are examined, and their potential applicant to neuronal cell death during development is discussed. Since most mammalian genes involved in cell death have other functions, it is possible that a novel set of death genes does not exist in mammals. Instead, the genes identified may serve to link an initial stimulus to die with the cellular events that actually cause death, primarily by providing regulatory signals that direct the decision. The idea of cell death as a response to conflicting growth regulatory signals, initially derived from studies on cycling, non-neuronal cells, is applied to proliferating neuronal precursors and postmitotic neurons. How neuronal death during development might be the outcome of conflicting signals, and how retinoblastoma protein might negotiate "death by conflict" in different populations of neurons is discussed.

Much is known about the morphological development of mammalian retinal ganglion cells. However, relatively little is understood about the mechanisms that direct dendritic development and determine ganglion cell morphology, mosaic organization, and foveal development. In the following, we review current data on primate retinal ganglion cell development and integrate it with information from other species into a general model of dendritic development. Furthermore, we propose that this model not only explains ganglion cell dendritic development, but also accounts for the establishment of retinal ganglion cell mosaics and the timing of foveal formation.

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.

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.

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.

Integrins and cell adhesion molecules (CAMs) are important neuronal receptors mediating substrate-induced axon growth. Signaling of axon growth through these receptors involves both regulation of tyrosine phosphorylation and transient increases in intracellular Ca2+. Many of the details concerning these signal transduction events and mechanisms through which they regulate effectors of axon growth are poorly understood. This review discusses some of the gaps in our current knowledge, with suggestions on approaches to closing these gaps. Emphasis is on the role of tyrosine phosphatases in the regulation of axon growth, the origin and nature of Ca2+ signals produced by stimulation of CAMs and integrins, and possible links of these two pathways to cytoskeletal rearrangements and directed addition of plasma membrane.

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.

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.

Proteoglycans have long been recognized as participating in a number of biological activities ranging from structural roles to regulation of transcription. Versican is a large chondroitin sulfate proteoglycan expressed in several tissues, including the nervous system. Significant progress has been made in the understanding of the molecular structure and biological activity of versican. The progress is largely due to the application of recombinant DNA methodology and the generation of domain-specific anti-versican antibodies. In the central and peripheral nervous system, versican is expressed by glial cells and is implicated in the regulation of cell adhesion, migration, pattern formation, and regeneration.