Retrograde transport of neurotrophins: fact and function

Retrograde signals generated by nerve growth factor (NGF) and other neurotrophins promote the survival of appropriately connected neurons during development, and failure to obtain sufficient retrograde signals may contribute to neuronal death occurring in many neurodegenerative diseases. The discovery over 25 years ago that NGF supplied to the axon terminals is retrogradely transported to the cell bodies suggested that NGF must reach the cell body to promote neuronal survival. Research during the intervening decades has produced a refinement of this hypothesis. The current hypothesis is that NGF bound to TrkA at the axon terminal is internalized into signaling endosomes, with NGF in their lumens bound to phosphorylated TrkA in their membranes, which are retrogradely transported to the cell bodies, where TrkA activates downstream signaling molecules that promote neuronal survival and regulate many aspects of neuronal gene expression. This model has been extrapolated to retrograde signaling by all neurotrophins. We consider the evidence for this model, focusing on results of experiments with neurons in compartmented cultures. Results to date indicate that while the transport of signaling endosomes containing NGF bound to TrkA may carry retrograde signals, retrograde survival signals can be carried by another mechanism that is activated by NGF at the axon terminal surface and travels to the cell body unaccompanied by the NGF that initiated it. It is hypothesized that multiple mechanisms of retrograde signaling exist and function under different circumstances. The newly discovered potential for redundancy in retrograde signaling mechanisms can complicate the interpretation of experimental results.     

Chloroplast-to-nucleus communication: Current knowledge,experimental strategies and relationship to drought stress signaling

In order for plant cells to function efficiently under different environmental conditions, chloroplastic processes have to be tightly regulated by the nucleus. It is widely believed that there is inter-organelle communication from the chloroplast to the nucleus, called retrograde signaling. Although some pathways of communication have been identified, the actual signals that move between the two cellular compartments are largely unknown. This review provides an overview of retrograde signaling including its importance to the cell, candidate signals, recent advances and current experimental systems. In addition, we highlight the potential of using drought stress as a model for studying retrograde signaling.Key words: retrograde, chloroplast, signals, drought, stress, high light, abiotic, excess light, photosynthesis     

From snails to sciatic nerve: Retrograde injury signaling from axon to soma in lesioned neurons

The cell body of a lesioned neuron must receive accurate and timely information on the site and extent of axonal damage, in order to mount an appropriate response. Specific mechanisms must therefore exist to transmit such information along the length of the axon from the lesion site to the cell body. Three distinct types of signals have been postulated to underlie this process, starting with injury-induced discharge of axon potentials, and continuing with two distinct types of retrogradely transported macromolecular signals. The latter include, on the one hand, an interruption of the normal supply of retrogradely transported trophic factors from the target; and on the other hand activated proteins emanating from the injury site. These activated proteins are termed "positive injury signals", and are thought to be endogenous axoplasmic proteins that undergo post-translational modifications at the lesion site upon axotomy, which then target them to the retrograde transport system for trafficking to the cell body. Here, we summarize the work to date supporting the positive retrograde injury signal hypothesis, and provide some new and emerging proteomic data on the system. We propose that the retrograde positive injury signals form part of a complex that is assembled by a combination of different processes, including post-translational modifications such as phosphorylation, regulated and transient proteolysis, and local axonal protein synthesis.     

Protein kinase signaling in synaptic plasticity and memory

The relay of extracellular signals into changes in cellular physiology involves a Byzantine array of intracellular signaling pathways, of which cytoplasmic protein kinases are a crucial component. In the nervous system, a great deal of effort has focused on understanding the conversion of patterns of synaptic activity into long-lasting changes in synaptic efficacy that are thought to underlie memory. The goal is both to understand synaptic plasticity mechanisms, such as long-term potentiation, at a molecular level and to understand the relationship of these synaptic mechanisms to behavioral memory. Although both involve the activation of multiple signaling pathways, recent studies are beginning to define discrete roles and mechanisms for individual kinases in the different temporal phases of both synaptic and behavioral plasticity.     

Endosome-mediated retrograde axonal transport of P2X3 receptor signals in primary sensory neurons

Neurotrophins and their receptors adopt signaling endosomes to transmit retrograde signals. However, the mechanisms of retrograde signaling for other ligand/receptor systems are poorly understood. Here, we report that the signals of the purinergic (P)2X(3) receptor, an ATP-gated ion channel, are retrogradely transported in dorsal root ganglion (DRG) neuron axons. We found that Rab5, a small GTPase, controls the early sorting of P2X(3) receptors into endosomes, while Rab7 mediates the fast retrograde transport of P2X(3) receptors. Intraplantar injection and axonal application into the microfluidic chamber of α, β-methylene-ATP (α, β-MeATP), a P2X selective agonist, enhanced the endocytosis and retrograde transport of P2X(3) receptors. The α, β-MeATP-induced Ca(2+) influx activated a pathway comprised of protein kinase C, rat sarcoma viral oncogene and extracellular signal-regulated protein kinase (ERK), which associated with endocytic P2X(3) receptors to form signaling endosomes. Disruption of the lipid rafts abolished the α, β-MeATP-induced ERK phosphorylation, endocytosis and retrograde transport of P2X(3) receptors. Furthermore, treatment of peripheral axons with α, β-MeATP increased the activation level of ERK and cAMP response element-binding protein in the cell bodies of DRG neurons and enhanced neuronal excitability. Impairment of either microtubule-based axonal transport in vivo or dynein function in vitro blocked α, β-MeATP-induced retrograde signals. These results indicate that P2X(3) receptor-activated signals are transmitted via retrogradely transported endosomes in primary sensory neurons and provide a novel signaling mechanism for ligand-gated channels.     

Modeling the signaling endosome hypothesis: Why a drive to the nucleus is better than a (random) walk

Background  

Information transfer from the plasma membrane to the nucleus is a universal cell biological property. Such information is generally encoded in the form of post-translationally modified protein messengers. Textbook signaling models typically depend upon the diffusion of molecular signals from the site of initiation at the plasma membrane to the site of effector function within the nucleus. However, such models fail to consider several critical constraints placed upon diffusion by the cellular milieu, including the likelihood of signal termination by dephosphorylation. In contrast, signaling associated with retrogradely transported membrane-bounded organelles such as endosomes provides a dephosphorylation-resistant mechanism for the vectorial transmission of molecular signals. We explore the relative efficiencies of signal diffusion versus retrograde transport of signaling endosomes.     

Roof plate-dependent patterning of the vertebrate dorsal central nervous system

In the vertebrate central nervous system (CNS), diverse cellular types are generated in response to inductive signals provided by specialized cellular groups that act as organizing centers. The roof plate is a critical dorsal signaling center that occupies the dorsal midline of the developing CNS along its entire anterior-posterior axis. During caudal neural tube development, the roof plate produces proteins of the Bmp and Wnt families controlling proliferation, specification, migration, and axon guidance of adjacent dorsal interneurons. Although primarily investigated in the developing spinal cord, a growing number of studies indicate that roof plate-derived signals are also critical for the patterning of dorsal structures in more rostral regions of CNS including the hindbrain, diencephalon and telencephalon. In this review, we discuss recent progress towards understanding the molecular and cellular mechanisms of roof plate-dependent patterning of the dorsal CNS.     

Long-distance retrograde neurotrophic signaling

The retrograde communication of neurotrophic signals from axon terminals to neuron cell bodies is crucial for neuron survival and plasticity. Several mechanisms have been proposed in the past, but recent evidence strongly supports the hypothesis that the retrograde propagation of self-regenerating signaling organelles, derived from the endocytosis of activated neurotrophin-bound receptor tyrosine kinases, is the primary mechanism responsible for this long-distance communication.     

Control of grain size by G protein signaling in rice

Heterotrimeric G proteins are involved in multiple cellular processes in eukaryotes by sensing and transducing various signals. G protein signaling in plants is quite different from that in animals, and the mechanisms of plant G protein signaling are still largely unknown. Several recent studies have provided new insights into the mechanisms of G protein signaling in rice grain size and yield control. In this review,we summarize recent advances on the function of G proteins in rice grain size control and discuss the potential genetic and molecular mechanisms of plant G protein signaling.     

Approaches to measuring calcium in zebrafish: focus on neuronal development

Calcium ions are known to act as important cellular signals during nervous system development. In vitro studies have provided significant information on the role of calcium signals during neuronal development; however, the function of this messenger in nervous system maturation in vivo remains to be established. The zebrafish has emerged as a valuable model for the study of vertebrate embryogenesis. Fertilisation is external and the rapid growth of the transparent embryo, including development of internal organs, can be observed easily making it well suited for imaging studies. The developing nervous system is relatively simple and has been well characterised, allowing individual neurons to be identified. Using the zebrafish model, both intracellular and intercellular calcium signals throughout embryonic development have been characterised. This review summarises technical approaches to measure calcium signals in developing embryonic and larval zebrafish, and includes recent developments that will facilitate the study of calcium signalling in vivo. The application of calcium imaging techniques to investigate the action of this messenger during embryogenesis in intact zebrafish is illustrated by discussion of their contribution to our understanding of neuronal development in vivo.     

Redox signaling in central neural regulation of cardiovascular function

One of the most prominent concepts to emerge in cardiovascular research over the past decade, especially in areas focused on angiotensin II (AngII), is that reactive oxygen species (ROS) are critical signaling molecules in a wide range of cellular processes. Many of the physiological effects of AngII are mediated by ROS, and alterations in AngII-mediated redox mechanisms are implicated in cardiovascular diseases such as hypertension and atherosclerosis. Although most investigations to date have focused on the vasculature as a key player, the nervous system has recently begun to gain attention in this field. Accumulating evidence suggests that ROS have important effects on central neural mechanisms involved in blood pressure regulation, volume homeostasis, and autonomic function, particularly those that involve AngII signaling. Furthermore, oxidant stress in the central nervous system is implicated in the neuro-dysregulation associated with some forms of hypertension and heart failure. The main objective of this review is to discuss the recent progress and prospects for this new field of central redox signaling in cardiovascular regulation, while also addressing the molecular tools that have spurred it forward.     

Nervous system pathology: the fibrin perspective

Studies of extracellular matrix (ECM) biology in the nervous system have mainly focused on laminin, fibronectin and tenascin-R, proteins that are present during nervous system development and normal function. However, during disease, fibrin, which physiologically is not present in the nervous tissue, is detected at nervous tissue lesions. This review summarizes evidence that correlates fibrin deposition with neuropathology and presents recent findings on cellular mechanisms and intracellular signaling pathways regulated by fibrin that might contribute to nervous system disease.     

Nitric oxide as a regulator of neuronal motility and regeneration in the locust embryo

Nitric oxide (NO) is known as a gaseous messenger in the nervous system. It plays a role in synaptic plasticity, but also in development and regeneration of nervous systems. We have studied the function of NO and its signaling cascade via cyclic GMP in the locust embryo. Its developing nervous system is well suited for pharmacological manipulations in tissue culture. The components of this signaling pathway are localized by histochemical and immunofluorescence techniques. We have analyzed cellular mechanisms of NO action in three examples: 1. in the peripheral nervous system during antennal pioneer axon outgrowth, 2. in the enteric nervous system during migration of neurons forming the midgut nerve plexus, and 3. in the central nervous system during axonal regeneration of serotonergic neurons after axotomy. In each case, internally released NO or NO-induced cGMP synthesis act as permissive signals for the developmental process. Carbon monoxide (CO), as a second gaseous messenger, modulates enteric neuron migration antagonistic to NO.     

Retrograde regulation in the CNS; neuron-specific interpretations of TGF-beta signaling

Retrograde signals influence neuronal survival, differentiation, synaptogenesis, and plasticity. Several recent papers describe novel roles for the well-studied TGF-beta pathway in retrograde synaptic signaling. While each dissects spatial and molecular aspects of TGF-beta signaling in a specific synaptic context, together these studies demonstrate that a specific retrograde signal may be interpreted in diverse, neuron-specific ways. Thus, a neuron's intrinsic properties and its other extrinsic signaling inputs determine its cellular and genomic response to TGF-beta.     

Plant abiotic stress response and nutrient use efficiency

Abiotic stresses and soil nutrient limitations are major environmental conditions that reduce plant growth, productivity and quality.Plants have evolved mechanisms to perceive these environmental challenges, transmit the stress signals within cells as well as between cells and tissues, and make appropriate adjustments in their growth and development in order to survive and reproduce. In recent years, significant progress has been made on many fronts of the stress signaling research, particularly in understanding the downstream signaling events that culminate at the activation of stress-and nutrient limitation-responsive genes, cellular ion homeostasis, and growth adjustment. However, the revelation of the early events of stress signaling, particularly the identification of primary stress sensors, still lags behind. In this review, we summarize recent work on the genetic and molecular mechanisms of plant abiotic stress and nutrient limitation sensing and signaling and discuss new directions for future studies.     

Wnt/β‐catenin signaling during early vertebrate neural development

The vertebrate central nervous system (CNS) is comprised of vast number of distinct cell types arranged in a highly organized manner. This high degree of complexity is achieved by cellular communication, including direct cell‐cell contact, cell‐matrix interactions, and cell‐growth factor signaling. Among the several developmental signals controlling the development of the CNS, Wnt proteins have emerged as particularly critical and, hence, have captivated the attention of many researchers. With Wnts' evolutionarily conserved function as primordial symmetry breaking signals, these proteins and their downstream effects are responsible for simultaneously establishing cellular diversity and tissue organization. With their expansive repertoire of secreted agonists and antagonists, cell surface receptors, signaling cascades and downstream biological effects, Wnts are ideally suited to control the complex processes underlying vertebrate neural development. In this review, we will describe the mechanisms by which Wnts exert their potent effects on cells and tissues and highlight the many roles of Wnt signaling during neural development, starting from the initial induction of the neural plate, the subsequent patterning along the embryonic axes, to the intricately organized structure of the CNS. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1239–1259, 2017