ReviewPurinergic signaling in neural development
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).
References (114)
- et al.
Involvement of P2 receptors in the growth and survival of neurons in the CNS
Pharmacol Ther
(2006) - et al.
Calcium waves propagate through radial glial cells and modulate proliferation in the developing neocortex
Neuron
(2004) - et al.
Trophic functions of nucleotides in the central nervous system
Trends Neurosci
(2009) - et al.
Do ATP and NO interact in the CNS?
Prog Neurobiol
(2008) - et al.
Src homology 3 binding sites in the P2Y2 nucleotide receptor interact with Src and regulate activities of Src, proline-rich tyrosine kinase 2, and growth factor receptors
J Biol Chem
(2004) - et al.
P2Y2 and TrkA receptors interact with Src family kinase for neuronal differentiation
Biochem Biophys Res Commun
(2006) - et al.
NPY mediates ATP-induced neuroproliferation in adult mouse olfactory epithelium
Neurobiol Dis
(2010) Liaisons dangereuses: P2X7 and the inflammasome
Trends Pharmacol Sci
(2007)- et al.
P2Y2 nucleotide receptors enhance α-secretase-dependent amyloid precursor protein processing
J Biol Chem
(2005) - et al.
Neuropeptide Y stimulates proliferation, migration and differentiation of neural precursors from the subventricular zone in adult mice
Neurobiol Dis
(2009)
Signalling from adenosine receptors to mitogen-activated protein kinases
Cell Signalling
Purinergic receptor activation inhibits mitogen-stimulated proliferation in primary neurospheres from the adult mouse subventricular zone
Mol Cell Neurosci
Purinergic signaling regulates neural progenitor cell expansion and neurogenesis
Dev Biol
Increase of intracellular Ca2+ by adenine and uracil nucleotides in human midbrain-derived neuronal progenitor cells
Cell Calcium
Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions
Cell
Gap junctions: multifaceted regulators of embryonic cortical development
Trends Neurosci
Radial glial cell heterogeneity—the source of diverse progeny in the CNS
Prog Neurobiol
Pathways of survival induced by NGF and extracellular ATP after growth factor deprivation
Prog Brain Res
Interaction between ATP and nerve growth factor signalling in the survival and neuritic outgrowth from PC12 cells
Neuroscience
Enhanced neurite outgrowth in PC12 cells mediated by connexin hemichannels and ATP
J Biol Chem
P2 receptor-stimulation influences axonal outgrowth in the developing hippocampus in vitro
Neuroscience
Expression of P2X purinoceptors during rat brain development and their inhibitory role on motor axon outgrowth in neural tube explant cultures
Neuroscience
Trophic effects of purines in neurons and glial cells
Prog Neurobiol
P2 receptor modulation and cytotoxic function in cultured CNS neurons
Neuropharmacology
Involvement of P2 purinoceptors in the regulation of DNA synthesis in the neural retina of chick embryo
Int J Dev Neurosci
Signal transduction pathways associated with ATP-induced proliferation of cell progenitors in the intact embryonic retina
Int J Dev Neurosci
ATP released via gap junction hemichannels from the pigment epithelium regulates neural retinal progenitor proliferation
Neuron
ATP controls cell cycle and induces proliferation in the mouse developing retina
Int J Dev Neurosci
ATP induces proliferation of retinal cells in culture via activation of PKC and extracellular signal-regulated kinase cascade
Int J Dev Neurosci
The genetic basis of mammalian neurulation
Nat Rev Genet
Neural crest specification: migrating into genomics
Nat Rev Neurosci
Purinoceptors: ontogeny and phylogeny
Drug Dev Res
Purinergic signalling in development
New insights into purinergic receptor signaling in neuronal differentiation, neuroprotection, and brain disorders
Purinergic Signal
Dynamic ATP signalling and neural development
J Physiol (London)
Ecto-nucleotidases in the nervous system
Novartis Found Symp
Synchronization of Ca2+oscillations: involvement of ATP release in astrocytes
FEBS J
Adenosine: an old drug newly discovered
Anesthesiology
Molecular physiology of P2X receptors
Physiol Rev
Molecular properties of P2X receptors
Pflugers Arch
International union of pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy
Pharmacol Rev
Evolutionary origins of the purinergic signalling system
Acta Physiol
Dinucleoside polyphosphates and their interaction with other nucleotide signaling pathways
Pflugers Arch Eur J Physiol
Dinucleoside polyphosphates: strong endogenous agonists of the purinergic system
Br J Pharmacol
G proteins in development
Nat Rev Mol Cell Biol
P2 receptors: intracellular signaling
Pflugers Arch
Gi-coupled P2Y-ADP receptor mediates GSK-3 phosphorylation and beta-catenin nuclear translocation in granule neurons
J Neurochem
P2 receptor-mediated stimulation of the PI3-K/Akt-pathway in vivo
Glia
ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors
Am J Physiol Cell Physiol
Interaction of P2 purinergic receptors with cellular macromolecules
Naunyn Schmiedebergs Arch Pharmacol
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