Target-derived Factors Research Articles

2045-LB: Target-Derived Factors Decrease Sympathetic Innervation of Brown Adipose Tissue in a Critical Period of Development

2045-LB: Target-Derived Factors Decrease Sympathetic Innervation of Brown Adipose Tissue in a Critical Period of Development

NGF Signaling in Endosomes.

During the development of the nervous system, neurons respond to diffusible cues secreted by target cells. Because such target-derived factors regulate development, maturation, and maintenance of axons as well as somatodendritic compartments, signals initiated at distal axons must be retrogradely transmitted toward cell bodies. Neurotrophins, including the nerve growth factor (NGF), provide one of the best-known examples of target-derived growth factors. The cell biological processes of endocytosis and retrograde trafficking of their Trk receptors from growth cones to cell bodies are key mechanisms by which target-derived neurotrophins influence neurons. Evidence accumulated over the past several decades has begun to uncover the molecular mechanisms of formation, transport, and biological functions of these specialized endosomes called "signaling endosomes."

Satellite glial cells modulate cholinergic transmission between sympathetic neurons.

Postganglionic sympathetic neurons and satellite glial cells are the two major cell types of the peripheral sympathetic ganglia. Sympathetic neurons project to and provide neural control of peripheral organs and have been implicated in human disorders ranging from cardiovascular disease to peripheral neuropathies. Here we show that satellite glia regulate synaptic activity of cultured postnatal sympathetic neurons, providing evidence for local ganglionic control of sympathetic drive. In addition to modulating neuron-to-neuron cholinergic neurotransmission, satellite glia promote synapse formation and contribute to neuronal survival. Examination of the cellular architecture of the rat sympathetic ganglia in vivo shows this regulation of neuronal properties takes place during a developmental period in which neuronal morphology and density are actively changing and satellite glia enwrap sympathetic neuronal somata. Cultured satellite glia make and release factors that promote neuronal activity and that can partially rescue the neurons from cell death following nerve growth factor deprivation. Thus, satellite glia play an early and ongoing role within the postnatal sympathetic ganglia, expanding our understanding of the contributions of local and target-derived factors in the regulation of sympathetic neuron function.

Retrograde apoptotic signaling by the p75 neurotrophin receptor

Neurotrophins are target-derived factors necessary for mammalian nervous system development and maintenance. They are typically produced by neuronal target tissues and interact with their receptors at axonal endings. Therefore, locally generated neurotrophin signals must be conveyed from the axon back to the cell soma. Retrograde survival signaling by neurotrophin binding to Trk receptors has been extensively studied. However, neurotrophins also bind to the p75 receptor, which can induce apoptosis in a variety of contexts. Selective activation of p75 at distal axon ends has been shown to generate a retrograde apoptotic signal, although the mechanisms involved are poorly understood. The present review summarizes the available evidence for retrograde proapoptotic signaling in general and the role of the p75 receptor in particular, with discussion of unanswered questions in the field. In-depth knowledge of the mechanisms of retrograde apoptotic signaling is essential for understanding the etiology of neurodegeneration in many diseases and injuries.

Nerve growth factor: a neuroimmune crosstalk mediator for all seasons.

Neurotrophic factors comprise a broad family of biomolecules - most of which are peptides or small proteins - that support the growth, survival and differentiation of both developing and mature neurons. The prototypical example and best-characterized neurotrophic factor is nerve growth factor (NGF), which is widely recognized as a target-derived factor responsible for the survival and maintenance of the phenotype of specific subsets of peripheral neurons and basal forebrain cholinergic nuclei during development and maturation. In addition to being active in a wide array of non-nervous system cells, NGF is also synthesized by a range of cell types not considered as classical targets for innervation by NGF-dependent neurons; these include cells of the immune-haematopoietic lineage and populations in the brain involved in neuroendocrine functions. NGF concentrations are elevated in numerous inflammatory and autoimmune states such as multiple sclerosis, chronic arthritis, systemic lupus erythematosus and mastocytosis, in conjunction with increased accumulation of mast cells. Intriguingly, NGF seems to be linked also with diabetic pathology and insulin homeostasis. Mast cells and NGF appear involved in neuroimmune interactions and tissue inflammation. As mast cells are capable of producing and responding to NGF, this suggests that alterations in mast cell behaviour could provoke maladaptive neuroimmune tissue responses, including those of an autoimmune nature. Moreover, NGF exerts a modulatory role on sensory nociceptive nerve physiology in the adult, which appears to correlate with hyperalgesic phenomena occurring in tissue inflammation. NGF can therefore be viewed as a multifactorial modulator of neuro-immune-endocrine functions.

Region-specific role of growth differentiation factor-5 in the establishment of sympathetic innervation.

BackgroundNerve growth factor (NGF) is the prototypical target-derived neurotrophic factor required for sympathetic neuron survival and for the growth and ramification of sympathetic axons within most but not all sympathetic targets. This implies the operation of additional target-derived factors for regulating terminal sympathetic axon growth and branching.ResultsHere report that growth differentiation factor 5 (GDF5), a widely expressed member of the transforming growth factor beta (TGFβ) superfamily required for limb development, promoted axon growth from mouse superior cervical ganglion (SCG) neurons independently of NGF and enhanced axon growth in combination with NGF. GDF5 had no effect on neuronal survival and influenced axon growth during a narrow window of postnatal development when sympathetic axons are ramifying extensively in their targets in vivo. SCG neurons expressed all receptors capable of participating in GDF5 signaling at this stage of development. Using compartment cultures, we demonstrated that GDF5 exerted its growth promoting effect by acting directly on axons and by initiating retrograde canonical Smad signalling to the nucleus. GDF5 is synthesized in sympathetic targets, and examination of several anatomically circumscribed tissues in Gdf5 null mice revealed regional deficits in sympathetic innervation. There was a marked, highly significant reduction in the sympathetic innervation density of the iris, a smaller though significant reduction in the trachea, but no reduction in the submandibular salivary gland. There was no reduction in the number of neurons in the SCG.ConclusionsThese findings show that GDF5 is a novel target-derived factor that promotes sympathetic axon growth and branching and makes a distinctive regional contribution to the establishment of sympathetic innervation, but unlike NGF, plays no role in regulating sympathetic neuron survival.

Regulation of Autocrine Signaling in Subsets of Sympathetic Neurons Has Regional Effects on Tissue Innervation.

SummaryThe regulation of innervation by target-derived factors like nerve growth factor (NGF) is the cornerstone of neurotrophic theory. Whereas autocrine signaling in neurons affecting survival and axon growth has been described, it is difficult to reconcile autocrine signaling with the idea that targets control their innervation. Here, we report that an autocrine signaling loop in developing mouse sympathetic neurons involving CD40L (TNFSF5) and CD40 (TNFRSF5) selectively enhances NGF-promoted axon growth and branching, but not survival, via CD40L reverse signaling. Because NGF negatively regulates CD40L and CD40 expression, this signaling loop operates only in neurons exposed to low levels of NGF. Consequently, the sympathetic innervation density of tissues expressing low NGF is significantly reduced in CD40-deficient mice, whereas the innervation density of tissues expressing high levels of NGF is unaffected. Our findings reveal how differential regulation of autocrine signaling in neurons has region-specific effects on axon growth and tissue innervation.

Estrogen and female reproductive tract innervation: cellular and molecular mechanisms of autonomic neuroplasticity.

The female reproductive tract undergoes remarkable functional and structural changes associated with cycling, conception and pregnancy, and it is likely advantageous to both individual and species to alter relationships between reproductive tissues and innervation. For several decades, it has been appreciated that the mammalian uterus undergoes massive sympathetic axon depletion in late pregnancy, possibly representing an adaptation to promote smooth muscle quiescence and sustained blood flow. Innervation to other structures such as cervix and vagina also undergo pregnancy-related changes in innervation that may facilitate parturition. These tissues provide highly tractable models for examining cellular and molecular mechanisms underlying peripheral nervous system plasticity. Studies show that estrogen elicits rapid degeneration of sympathetic terminal axons in myometrium, which regenerate under low-estrogen conditions. Degeneration is mediated by the target tissue: under estrogen's influence, the myometrium produces proteins repulsive to sympathetic axons including BDNF, neurotrimin, semaphorins, and pro-NGF, and extracellular matrix components are remodeled. Interestingly, nerve depletion does not involve diminished levels of classical sympathetic neurotrophins that promote axon growth. Estrogen also affects sympathetic neuron neurotrophin receptor expression in ways that appear to favor pro-degenerative effects of the target tissue. In contrast to the uterus, estrogen depletes vaginal autonomic and nociceptive axons, with the latter driven in part by estrogen-induced suppression of BMP4 synthesis. These findings illustrate that hormonally mediated physiological plasticity is a highly complex phenomenon involving multiple, predominantly repulsive target-derived factors acting in concert to achieve rapid and selective reductions in innervation.

Retinal Input Directs the Recruitment of Inhibitory Interneurons into Thalamic Visual Circuits

Inhibitory interneurons (INs) critically control the excitability and plasticity of neuronal networks, but whether activity can direct INs into specific circuits during development is unknown. Here, we report that in the dorsal lateral geniculate nucleus (dLGN), which relays retinal input to the cortex, circuit activity is required for the migration, molecular differentiation, and functional integration of INs. We first characterize the prenatal origin and molecular identity of dLGN INs, revealing their recruitment from an Otx2(+) neuronal pool located in the adjacent ventral LGN. Using time-lapse and electrophysiological recordings, together with genetic and pharmacological perturbation of retinal waves, we show that retinal activity directs the navigation and circuit incorporation of dLGN INs during the first postnatal week, thereby regulating the inhibition of thalamocortical circuits. These findings identify an input-dependent mechanism regulating IN migration and circuit inhibition, which may account for the progressive recruitment of INs into expanding excitatory circuits during evolution.

Glia cell line-derived neurotrophic factor mediates survival of murine sympathetic precursors

During embryonic development, neurons are first produced in excess, and final numbers are adjusted by apoptosis at later stages. Crucial to this end is the amount of target-derived growth factor available for the neurons. By this means, the target size correctly matches the innervating neuron number. This target-derived survival has been well studied for sympathetic neurons, and nerve growth factor (NGF) was identified to be the crucial factor for maintaining sympathetic neurons at late embryonic and early postnatal stages, with a virtual complete loss of sympathetic neurons in NGF knockout (KO) mice. This indicates that all sympathetic neurons are dependent on NGF. However, also different glia cell line-derived neurotrophic factor (GDNF) KO mice consistently presented a loss of sympathetic neurons. This was the rationale for investigating the role of GDNF for sympathetic precursor/neuron survival. Here we show that GDNF is capable of promoting survival of 30% sympathetic precursors dissociated at E13. This is in line with data from GDNF KOs in which a comparable sympathetic neuron loss was observed at late embryonic stages, although the onset of the phenotype was unclear. We further present data showing that GDNF ligand and canonical receptors are expressed in sympathetic neurons especially at embryonic stages, raising the possibility of an autocrine/paracrine GDNF action. Finally, we show that GDNF also maintained neonatal sympathetic neurons (40%) cultured for 2 days. However, the GDNF responsiveness was lost at 5 days in vitro.

Scaling proprioceptor gene transcription by retrograde NT3 signaling.

Cell-type specific intrinsic programs instruct neuronal subpopulations before target-derived factors influence later neuronal maturation. Retrograde neurotrophin signaling controls neuronal survival and maturation of dorsal root ganglion (DRG) sensory neurons, but how these potent signaling pathways intersect with transcriptional programs established at earlier developmental stages remains poorly understood. Here we determine the consequences of genetic alternation of NT3 signaling on genome-wide transcription programs in proprioceptors, an important sensory neuron subpopulation involved in motor reflex behavior. We find that the expression of many proprioceptor-enriched genes is dramatically altered by genetic NT3 elimination, independent of survival-related activities. Combinatorial analysis of gene expression profiles with proprioceptors isolated from mice expressing surplus muscular NT3 identifies an anticorrelated gene set with transcriptional levels scaled in opposite directions. Voluntary running experiments in adult mice further demonstrate the maintenance of transcriptional adjustability of genes expressed by DRG neurons, pointing to life-long gene expression plasticity in sensory neurons.

Reciprocal Regulation of Axonal Filopodia and Outgrowth during Neuromuscular Junction Development

BackgroundThe assembly of the vertebrate neuromuscular junction (NMJ) is initiated when nerve and muscle first contact each other by filopodial processes which are thought to enable close interactions between the synaptic partners and facilitate synaptogenesis. We recently reported that embryonic Xenopus spinal neurons preferentially extended filopodia towards cocultured muscle cells and that basic fibroblast growth factor (bFGF) produced by muscle activated neuronal FGF receptor 1 (FGFR1) to induce filopodia and favor synaptogenesis. Intriguingly, in an earlier study we found that neurotrophins (NTs), a different set of target-derived factors that act through Trk receptor tyrosine kinases, promoted neuronal growth but hindered presynaptic differentiation and NMJ formation. Thus, here we investigated how bFGF- and NT-signals in neurons jointly elicit presynaptic changes during the earliest stages of NMJ development.Methodology/Principal FindingsWhereas forced expression of wild-type TrkB in neurons reduced filopodial extension and triggered axonal outgrowth, expression of a mutant TrkB lacking the intracellular kinase domain enhanced filopodial growth and slowed axonal advance. Neurons overexpressing wild-type FGFR1 also displayed more filopodia than control neurons, in accord with our previous findings, and, notably, this elevation in filopodial density was suppressed when neurons were chronically treated from the beginning of the culture period with BDNF, the NT that specifically activates TrkB. Conversely, inhibition by BDNF of NMJ formation in nerve-muscle cocultures was partly reversed by the overexpression of bFGF in muscle.ConclusionsOur results suggest that the balance between neuronal FGFR1- and TrkB-dependent filopodial assembly and axonal outgrowth regulates the establishment of incipient NMJs.

RNASeq profiling of UTR expression during neuronal plasticity

Background Neurons interact with, and are influenced by, tissues that are remote from the cell body. For example, sensory neuron cell bodies are located within peri-spinal ganglia but are connected to both the spinal cord and skin via their axons projecting through dorsal roots and peripheral nerves. Biochemical signals from anatomical compartments (spinal cord / root / ganglion / nerve / skin) modulate the molecular biology of neurons which can respond to signals from any/all of these remote regions. One mechanism by which neurons respond to these signals and interact with their targets is by actively transporting mRNA to that region. There, the mRNA is translated to produce protein at locally-determined positions and times. A growing body of evidence shows that untranslated regions (UTRs) of genes are important for this targeting. For example, 3’-UTRs contain 50nt “zip code” consensus binding sites for cis-acting zip code-binding proteins (ZPBs) that drive axonal targeting of mRNA [1]. We therefore hypothesized that gene expression during collateral sprouting, an axonal growth process that is highly responsive to target-derived factors, might involve differential regulation of UTR components.

Motoneuron programmed cell death in response to proBDNF.

Motoneurons (MN) as well as most neuronal populations undergo a temporally and spatially specific period of programmed cell death (PCD). Several factors have been considered to regulate the survival of MNs during this period, including availability of muscle-derived trophic support and activity. The possibility that target-derived factors may also negatively regulate MN survival has been considered, but not pursued. Neurotrophin precursors, through their interaction with p75(NTR) and sortilin receptors have been shown to induce cell death during development and following injury in the CNS. In this study, we find that muscle cells produce and secrete proBDNF. ProBDNF through its interaction with p75(NTR) and sortilin, promotes a caspase-dependent death of MNs in culture. We also provide data to suggest that proBDNF regulates MN PCD during development in vivo.

Intra-axonal Translation of SMAD1/5/8 Mediates Retrograde Regulation of Trigeminal Ganglia Subtype Specification

In many cases, neurons acquire distinct identities as their axons navigate toward target cells and encounter target-derived signaling molecules. These molecules generate retrograde signals that activate subtype-specific gene transcription. Mechanisms by which axons convert the complex milieu of signaling molecules into retrograde signals are not fully understood. Here, we examine retrograde signaling mechanisms that specify neuronal identity in the trigeminal ganglia, which relays sensory information from the face to the brain. We find that neuron specification requires the sequential action of two target-derived factors, BDNF and BMP4. BDNF induces the translation of axonally localized SMAD1/5/8 transcripts. Axon-derived SMAD1/5/8 is translocated to the cell body, where it is phosphorylated to a transcriptionally active form by BMP4-induced signaling endosomes and mediates the transcriptional effects of target-derived BDNF and BMP4. Thus, local translation functions as a mechanism by which coincident signals are converted into a retrograde signal that elicits a specific transcriptional response.

Neurotrophin-4 modulates the mechanotransducer Cav3.2 T-type calcium current in mice down-hair neurons

The T-type Ca2+ channel Cav3.2 is expressed in nociceptive and mechanosensitive sensory neurons. The mechanosensitive D-hair (down-hair) neurons, which innervate hair follicles, are characterized by a large-amplitude Cav3.2 T-current involved in the amplification of slow-moving stimuli. The molecules and signalling pathways that regulate T-current expression in mechanoreceptors are unknown. In the present study, we investigated the effects of NT-4 (neurotrophin-4) on Cav3.2 T-current expression in D-hair neurons in vitro. Interruption of the supply of NT-4 with peripheral nerve axotomy induced a non-transcriptional decrease in the T-current amplitude of fluorogold-labelled axotomized sensory neurons. The T-current amplitude was restored by incubation with NT-4. Deletion of NT-4 through genetic ablation resulted in a similar selective loss of the large-amplitude T-current in NT-4-/- sensory neurons, which was rescued by the addition of NT-4. NT-4 had no effect on the T-current in Cav3.2-/- D-hair neurons. Neither the biophysical properties of the T-current nor the transcript expression of Cav3.2 were modified by NT-4. Pharmacological screening of signalling pathways activated under the high-affinity NT-4 receptor TrkB (tropomyosin receptor kinase B) identified a role for PI3K (phosphoinositide 3-kinase) in the potentiation of T-current. The results of the present study demonstrate the post-transcriptional up-regulation of the Cav3.2 T-current through TrkB activation and identify NT-4 as a target-derived factor that regulates the mechanosensitive function of D-hair neurons through expression of the T-current.

IL-1β inhibits axonal growth of developing sympathetic neurons

Several secreted proteins facilitate the growth and guidance of sympathetic axons to their target organs during development. Here we show that IL-1β, a key regulator of inflammation in the immune system, inhibits axonal growth and branching from cultured sympathetic neurons at a stage in development when their axons are ramifying within their targets in vivo. IL-1β is synthesised in sympathetic ganglia and its targets at this stage, and IL-1β protein is detectable in the axons and perikarya of the innervating neurons. It acts directly on developing axons to inhibit their growth via NF-κB signalling. These findings show that IL-1β is a novel locally, and target-derived factor that can regulate the extent of sympathetic axon growth during the late embryonic and early postnatal period in developing rat sympathetic neurons.

Weaving the neuronal net with target‐derived fibroblast growth factors

Fibroblast growth factors (FGFs) are a large family of secreted growth factors that are involved in the development, regeneration and repair of various tissues. In the nervous system, FGFs have been implicated in early developmental processes, such as neural induction, proliferation and patterning. Accumulating data indicate that FGFs are also important for the formation of functional neural networks. The role of FGFs in axon guidance, target recognition and synaptic differentiation as target-derived factors, and how they cooperate with cell adhesion molecules that are also involved in the wiring of the nervous system are the focus of this review.

Complementary Actions of BDNF and Neurotrophin-3 on the Firing Patterns and Synaptic Composition of Motoneurons

Neurotrophins, as target-derived factors, are essential for neuronal survival during development, but during adulthood, their scope of actions widens to become also mediators of synaptic and morphological plasticity. Target disconnection by axotomy produces an initial synaptic stripping ensued by synaptic rearrangement upon target reinnervation. Using abducens motoneurons of the oculomotor system as a model for axotomy, we report that trophic support by brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) or a mixture of both, delivered to the stump of severed axons, results in either the prevention of synaptic stripping when administered immediately after lesion or in a promotion of reinnervation of afferents to abducens motoneurons once synaptic stripping had occurred, in concert with the recovery of synaptic potentials evoked from the vestibular nerve. Synaptotrophic effects, however, were larger when both neurotrophins were applied together. The axotomy-induced reduction in firing sensitivities related to eye movements were also restored to normal values when BDNF and NT-3 were administered, but discharge characteristics recovered in a complementary manner when only one neurotrophin was used. This is the first report to show selective retrograde trophic dependence of circuit-driven firing properties in vivo indicating that NT-3 restored the phasic firing, whereas BDNF supported the tonic firing of motoneurons during eye movement performance. Therefore, our data report a link between the synaptotrophic actions of neurotrophins, retrogradely delivered, and the alterations of neuronal firing patterns during motor behaviors. These trophic actions could be responsible, in part, for synaptic rearrangements that alter circuit stability and synaptic balance during plastic events of the brain.

GABA Specification in the Embryonic CNS: Genes, Activity and Target-Derived Factors

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