Review
Purinergic signaling in neural development

https://doi.org/10.1016/j.semcdb.2011.02.007Get rights and content

Abstract

Extracellular purine and pyrimidine compounds induce a multiplicity of cellular signal pathways that can induce multiple trophic functions. They interact with other low molecular weight messengers, growth factors, and extracellular matrix components. An increasing number of studies now provide evidence for a role of purinergic signaling in neural development, including progenitor cell proliferation, cell migration, neuronal and glial maturation and differentiation, and cell death and survival. This brief overview highlights recent developments supporting a contribution of purinergic signaling to embryonic and adult neurogenesis.

Introduction

The development of the nervous system requires a complex series of cellular programming and intercellular communication events that proceed from the early neural induction to the formation of a highly structured central and peripheral nervous system. The cells of the neural tube function as pluripotent stem cells and give rise to essentially all neurons and macroglia of the brain and spinal cord. At the junction between the neural tube and the ectoderm, the neural crest cells are formed, the origin of neurons and glia of the peripheral nervous system (sensory, enteric and autonomic ganglia) [1], [2].

Major steps involved in the formation of the fully wired and functional mature central and peripheral nervous system include the proliferation of the early progenitors, migration of young neurons, their differentiation and cell type specification, neuritogenesis with axon growth and guidance, synapse formation and stabilization, the death of neurons that failed to integrate successfully, and finally neural network formation. Similarly, gliogenesis involves proliferation, specification, migration and differentiation that require multiple pathways of genetic control and cellular communication.

A considerable number of cell surface-mediated signaling pathways, often involving specific spatial and temporal gradients, have been implicated in neural development. They emphasize the importance of intercellular communication mechanisms in the control or the fine tuning of specific developmental processes. Recent findings suggest that nucleotides and adenosine act as intercellular mediators in vertebrate neurogenesis. Aspects of the role of nucleotides and nucleosides in nervous system development have previously been reviewed [3], [4], [5], [6], [7].

Section snippets

The reach of purinergic signaling

Nucleotides are short-lived and short-ranged extracellular signal molecules [8]. They do not generally qualify as long distance cues and their effects are largely restricted to autocrine and paracrine signaling. There are, however exceptions to this role since nucleotide-mediated glial Ca2+ waves can spread over considerable distances and propagate nucleotide signaling [9] (Fig. 1). Moreover, Ca2+ waves may spread through highly polar cells such as the radial glial cells and propagate

Subtypes of ionotropic and metabotropic P2 receptors

Nucleotides exert rapid effects via ionotropic P2X receptors. These homomeric or heteromeric receptors (seven subtypes, P2X1-7) are stimulated by ATP, represent Na+, K+, and Ca2+ permeable ion channels, and induce rapid changes in membrane potential [12], [13]. More long-lasting and trophic functions are generally exerted by the G protein-coupled P2Y receptors that can activate a considerable variety of intracellular signaling pathways, including gene activation [14], [15]. The eight mammalian

P1 adenosine receptors

Adenosine acts at G protein-coupled purinergic P1 receptors (A1, A2A, A2B, A3), similarly exerting multiple trophic functions [43], [44]. A1 and A3 receptors typically couple to Gi whereas A2A and A2B receptors are coupled to Gs, increasing the production of cAMP. But all of these receptors also couple to additional effectors including MAP kinases [43]. It should be noted that the effects mediated by ATP or ADP and their rapidly formed hydrolysis product adenosine need to be clearly

Ectonucleotidases

The life span of extracellular nucleotides is controlled by cell surface-located ectonucleotidases, enzymes of the plasma membrane with an extracellularly oriented catalytic site. Ectonucleotidases comprise several protein families with differing substrate specificities and partially overlapping tissue distribution. Ectonucleoside triphosphate diphosphohydrolases (NTPDases) and ectonucleotide pyrophosphatase/phosphodiesterases hydrolyze nucleoside tri- and/or diphosphates to the respective

Developmental regulation of nucleotide receptor and ectonucleotidase expression and nucleotide release

Signaling pathways employing extracellular nucleotides and adenosine are expressed early on during embryonic development of the central and peripheral nervous system, including the sensory organs. This concerns both P1 and P2 receptors and various types of ectonucleotidases. P2 receptors and TNAP are already expressed by embryonic stem cells. Interestingly, the expression of specific subtypes of receptors or enzymes can vary with developmental stage or is transient, suggesting that nucleotides

Studies on neural progenitor cells in vitro identify purinergic control mechanisms

Neurospheres represent a widely used in vitro cellular system for the analysis of the properties of neural stem cells [48]. They can be isolated from the mitotically active lateral ventricle walls of fetal, postnatal or adult mammalian brains. Under appropriate culture conditions and in the presence of growth factors the highly proliferative cells can be propagated as floating cell aggregates (neurospheres) or as adherent cells. They represent at least in part pluripotent stem cells, with the

Investigations on brain slices highlight the functional involvement of P2Y receptor signaling in fetal brain development

Brain slices derived from embryonic brain carry most of the features of intact brain tissue in situ and represent an important system for analyzing mechanisms of neurogenesis. A major focus has been on the development of the forebrain with its laminar structure. The cortical projection neurons are generated from neural precursors situated in an embryonic proliferative zone at the ventricle surface (Fig. 4). Young neurons borne in this region migrate into the overlaying cortical tissue. Of

Differential effects on neuronal differentiation and neurite growth

The potential of nucleotides to increase or inhibit neuronal differentiation and neurite or axon outgrowth has received considerable attention. Various cell lines that can be induced to acquire a neuron-like phenotype have been investigated. These include murine P19 embryonal carcinoma cells, murine neuroblastoma Neuro-2a cells, human SH-SY5Y neuroblastoma cells, or rat pheochromocytoma 12 (PC12) cells (reviewed in [6], [20], [46]). It is not unexpected that the receptor specificity and outcome

Cell death and survival can be differentially affected

Cell death is a general feature of the developing nervous system. Neurogenesis is accompanied by a tremendous loss of overproduced neurons and glia that either have lost trophic support or are subjected to specific death-initiating signals. As for neuronal differentiation, nucleotides were found to exert differential and opposing effects on both cell survival and cell death, depending on the system investigated [85]. In a variety of cellular systems extracellular ATP has been shown to induce

Nucleotide signaling in the developing neural retina

Retinal development bares close similarities to the ventricular zone of other parts of the developing nervous system. Retinal progenitor cells are multipotent and give rise to all neuronal and glial cell types of the retina [93]. Most of the evidence concerning the impact of ATP on the neural retina is derived from studies on the chicken retina. The retinal ventricular zone in intact explants of the embryonic chick retina undergoes spontaneous Ca2+ waves. Both, exogenous UTP and ATP elicit Ca2+

Nucleotides stimulate neurogenesis in the olfactory epithelium

Neurogenesis in the rodent olfactory epithelium predominates during embryonic development but continues in the adult. New olfactory receptor neurons can be formed from basal progenitor cells that constitute the proliferative and multipotent cells of this system throughout adulthood. Recent investigations provide evidence that nucleotides can participate in the control of proliferation and neuronal differentiation in the mouse olfactory epithelium. ATP and UTP increased incorporation of the

A role for nucleotides in adult neurogenesis

In the adult mammalian brain, neurogenesis persists in two restricted neurogenic niches: the adult SVZ (also referred to as subependymal zone, SEZ) of the lateral ventricles and the subgranular layer of the hippocampal dentate gyrus. Both regions house radial glia-derived astrocyte-like precursors [105]. Young neurons (neuroblasts) derived from the stem cells in the SEZ migrate via the olfactory stream to the olfactory bulb, where they either undergo apoptosis or differentiate into

Purinergic control of gliogenesis

Increasing evidence suggests that the formation and maturation of oligodendrocytes and Schwann cells, of NG2 cells [112] and of microglia underlie purinergic control mechanisms. Since several aspects of this have previously been reviewed [20], [46], [81], [113] and are dealt with by other articles in this issue, gliogenesis will not be discussed (see contributions by Butt and Fields).

Conclusion

The cellular elements involved in the neurogenesis pathway are equipped with a considerable variety of nucleotide and adenosine receptors that are expressed already at early developmental stages. Within the past years, this capacity has received increasing attention and the functional significance of nucleotide and adenosine signaling in both the generation of neurons and glial cells and of the histological and functional mature nervous system is being elaborated. While still patchy, the

Acknowledgement

This work was supported by Deutsche Forschungsgemeinschaft (140/17-4; Zi 140/18-1).

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