More than being protective: functional roles for TGF-β/activin signaling pathways at central synapses

doi:10.1016/j.tins.2011.06.002

Trends in Neurosciences

Volume 34, Issue 8, August 2011, Pages 421-429

https://doi.org/10.1016/j.tins.2011.06.002 Get rights and content

It is becoming increasingly clear that members of the transforming growth factor-β (TGF-β) family have roles in the central nervous system that extend beyond their well-established roles as neurotrophic and neuroprotective factors. Recent findings have indicated that the TGF-β signaling pathways are involved in the modulation of both excitatory and inhibitory synaptic transmission in the adult mammalian brain. In this review, we discuss how TGF-β, bone morphogenetic protein and activin signaling at central synapses modulate synaptic plasticity, cognition and affective behavior. We also discuss the implications of these findings for the molecular understanding and potential treatment of neuropsychiatric diseases, such as anxiety, depression and other neurological disorders.

Introduction

The human transforming growth factor-β (TGF-β) family comprises a group of 33 secreted proteins that act as morphogens and regulate numerous developmental processes, as well as adult tissue homeostasis and tissue repair 1, 2, 3, 4, 5. The family includes the TGF-βs themselves, activins, nodal, bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs). It has been well established, mainly from work on the Drosophila neuromuscular junction (NMJ), that BMPs are crucial for the formation and function of this highly specialized synapse 6, 7, 8. In addition, many components of the BMP signaling pathway are expressed in the mammalian brain 9, 10, 11, and growing evidence suggests that such signaling plays important roles not only during development, but also in the adult brain. Functional roles for TGF-β and activin signaling pathways in the regulation of neurotransmission in the adult brain under physiological as well as pathophysiological conditions have also emerged in the past several years. In this review, we discuss recent findings for mammalian members of the TGF-β, activin and BMP subfamilies at central synapses in the mammalian brain.

Section snippets

The TGF-β family and associated signaling pathways

TGF-βs are synthesized as pre-pro-proteins, consisting of an N-terminal signal peptide, a longer pro-peptide, followed by a shorter C-terminal mature polypeptide. In the trans-Golgi, the precursor proteins are sorted to the secretory pathway, where they are cleaved by a furin-like protease into the pro-peptide and mature peptide; these are then secreted and targeted to the extracellular matrix. The mature forms are characterized by nine cysteine residues, eight of which form four intramolecular

TGF-β

In the nervous system, TGF-β2 and TGF-β3 are found in neural progenitor cells, in differentiating neurons and radial glial cells, and later in mature astrocytes and numerous neuron populations. TGF-β1 is first expressed in the meninges and the choroid plexus 18, 19 and also later in glial cells. Furthermore, TGF-β1 and TGF-β2 are known to be upregulated in neurons after traumatic spinal cord injury 20, 21.

TGF-β members are well known for their capacity to regulate cell proliferation in a

TGF-β

TGF-β isoforms are not only sorted into the constitutive secretory pathway, but also into the regulated pathway of secretion in chromaffin cells as well as in hippocampal neurons 59, 60. Furthermore, neuronal activity regulates TGF-β release and TGF-β2 and -β3 expression in cultured mouse hippocampal neurons [60]. Depolarization induced by high concentrations of potassium chloride caused Smad2 translocation into the nucleus and upregulation of TGF-β inducible early gene (Tieg1) expression [60].

Tuning synapses versus protecting neurons

After highlighting the functional importance of TGF-β/activin signaling pathways at central synapses, the question arises as to how these physiological functions of TGF-β family members relate to their well-known neuroprotective effects in the injured and degenerating brain (Box 2).Do TGF-β signaling pathways affect synaptic properties to attenuate neuronal damage, or are synaptic tuning and neuronal survival achieved through different pathways? Given that activin had been reported to shield

Conclusions

Although the impact of BMP signaling on central synaptic functions is only beginning to be deciphered, a sizable body of evidence implicates TGF-β/activin signaling pathways in the homeostatic regulation of excitatory and inhibitory synapses in the intact CNS, with particular emphasis on the mechanisms underlying short-term and long-term plasticity. Electrophysiological studies using transgenic mice demonstrate that malfunctions in TGF-β/activin signaling cascades might disturb various features

Acknowledgments

We thank Sabine Werner (Institute of Cell Biology, ETH Zurich, Switzerland) for helpful comments on the manuscript. Research in our laboratories was supported by the Deutsche Forschungsgemeinschaft (SFB 406 and SFB 780 to KK, Un 34/25 to KU, SFB 391 and Al 294/9 to CA) and the Bundesministerium für Bildung und Forschung (CA).

References (103)

S. Werner et al.
Roles of activin in tissue repair, fibrosis, and inflammatory disease
Cytokine Growth Factor Rev.
(2006)
V. Dudu
Postsynaptic mad signaling at the Drosophila neuromuscular junction
Curr. Biol.
(2006)
V. Bayat
The BMP signaling pathway at the Drosophila neuromuscular junction and its links to neurodegenerative diseases
Curr. Opin. Neurobiol.
(2011)
Y. Xia et al.
The biology of activin: recent advances in structure, regulation and function
J. Endocrinol.
(2009)
K. Unsicker
Transforming growth factor beta isoforms in the adult rat central and peripheral nervous system
Neuroscience
(1991)
K. Krieglstein
Neural functions of the transforming growth factors beta
Int. J. Dev. Neurosci.
(1995)
Y.X. Zhou
Cerebellar deficits and hyperactivity in mice lacking Smad4
J. Biol. Chem.
(2003)
K. Abe
Transforming growth factor-beta 1 promotes re-elongation of injured axons of cultured rat hippocampal neurons
Brain Res.
(1996)
J.J. Yi
TGF-beta signaling specifies axons during brain development
Cell
(2010)
M. Yamagata
Synaptic adhesion molecules
Curr. Opin. Cell Biol.
(2003)

A.B. Roberts

TGF-beta: regulation of extracellular matrix

Kidney Int.

(1992)

C.J. Gottardi et al.

Adhesion signaling: how beta-catenin interacts with its partners

Curr. Biol.

(2001)

R. Klein

Excitatory Eph receptors and adhesive ephrin ligands

Curr. Opin. Cell Biol.

(2001)

F. Varoqueaux

Neuroligins determine synapse maturation and function

Neuron

(2006)

J.T. Henderson

The receptor tyrosine kinase EphB2 regulates NMDA-dependent synaptic function

Neuron

(2001)

I.M. Ethell

EphB/syndecan-2 signaling in dendritic spine morphogenesis

Neuron

(2001)

D.A. Lim

Noggin antagonizes BMP signaling to create a niche for adult neurogenesis

Neuron

(2000)

G. Kempermann

Activity-dependent regulation of neuronal plasticity and self repair

Prog. Brain Res.

(2000)

P. Lein

Osteogenic protein-1 induces dendritic growth in rat sympathetic neurons

Neuron

(1995)

K. Andreasson et al.

Induction of beta-A activin expression by synaptic activity and during neocortical development

Neuroscience

(1995)

M. Ishikawa

Involvement of the serum response factor coactivator megakaryoblastic leukemia (MKL) in the activin-regulated dendritic complexity of rat cortical neurons

J. Biol. Chem.

(2010)

Y. Iwahori

Activin exerts a neurotrophic effect on cultured hippocampal neurons

Brain Res.

(1997)

M. Sekiguchi

Neuron type-selective effects of activin on development of the hippocampus

Neurosci. Lett.

(2009)

H. Specht

Transforming growth factor beta2 is released from PC12 cells via the regulated pathway of secretion

Mol. Cell Neurosci.

(2003)

A. Lacmann

Activity-dependent release of transforming growth factor-beta in a neuronal network in vitro

Neuroscience

(2007)

K. Inokuchi

Increase in activin betaA mRNA in rat hippocampus during long-term potentiation

FEBS Lett.

(1996)

M.R. Muller

Transgenic mice expressing dominant-negative activin receptor IB in forebrain neurons reveal novel functions of activin at glutamatergic synapses

J. Biol. Chem.

(2006)

A. Kurisaki

Activin induces long-lasting N-methyl-d-aspartate receptor activation via scaffolding PDZ protein activin receptor interacting protein 1

Neuroscience

(2008)

T. Kitamura

Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory

Cell

(2009)

M. Antsiferova

Keratinocyte-derived follistatin regulates epidermal homeostasis and wound repair

Lab. Invest.

(2009)

C.A. Harrison

Antagonists of activin signaling: mechanisms and potential biological applications

Trends Endocrinol. Metab.

(2005)

C.C. Hong et al.

Applications of small molecule BMP inhibitors in physiology and disease

Cytokine Growth Factor Rev.

(2009)

Y. Shi et al.

Mechanisms of TGF-beta signaling from cell membrane to the nucleus

Cell

(2003)

P. Qiu

Interaction of Smad3 and SRF-associated complex mediates TGF-beta1 signals to regulate SM22 transcription during myofibroblast differentiation

J. Mol. Cell Cardiol.

(2003)

D.D. Wu

Expression of the activin axis and neuronal rescue effects of recombinant activin A following hypoxic-ischemic brain injury in the infant rat

Brain Res.

(1999)

P.E. Hughes

Administration of recombinant human Activin-A has powerful neurotrophic effects on select striatal phenotypes in the quinolinic acid lesion model of Huntington's disease

Neuroscience

(1999)

R. Gonzalez-Aparicio

Antiparkinsonian trophic action of glial cell line-derived neurotrophic factor and transforming growth factor beta1 is enhanced after co-infusion in rats

Exp. Neurol.

(2010)

E.M. De Robertis et al.

Dorsal–ventral patterning and neural induction in Xenopus embryos

Annu. Rev. Cell Dev. Biol.

(2004)

M. Affolter et al.

The Decapentaplegic morphogen gradient: from pattern formation to growth regulation

Nat. Rev. Genet.

(2007)

R. Derynck et al.

Differentiation plasticity regulated by TGF-beta family proteins in development and disease

Nat. Cell Biol.

(2007)

R. Derynck et al.

TGF-beta and the TGF-beta family

M. Packard

Wnts and TGF beta in synaptogenesis: old friends signalling at new places

Nat. Rev. Neurosci.

(2003)

T. Ebendal

Bone morphogenetic proteins and their receptors: potential functions in the brain

J. Neurosci. Res.

(1998)

S. Söderström

Expression of serine/threonine kinase receptors including the bone morphogenetic factor type II receptor in the developing and adult rat brain

Cell Tissue Res.

(1996)

I.C. Scott

Spatiotemporal expression patterns of mammalian chordin during postgastrulation embryogenesis and in postnatal brain

Dev. Dyn.

(2000)

P. Ten Dijke et al.

Extracellular control of TGFbeta signalling in vascular development and disease

Nat. Rev. Mol. Cell Biol.

(2007)

A. Moustakas et al.

The regulation of TGFbeta signal transduction

Development

(2009)

K. Miyazawa

Two major Smad pathways in TGF-beta superfamily signalling

Genes Cells

(2002)

E. Wiater et al.

Activins and inhibins

L.M. Bilezikjian

Pituitary actions of ligands of the TGF-beta family: activins and inhibins

Reproduction

(2006)

Cited by (109)

Tonic activin signaling shapes cellular and synaptic properties of CA1 neurons mainly in dorsal hippocampus
2023, iScience
Dorsal and ventral hippocampus serve different functions in cognition and affective behavior, but the underpinnings of this diversity at the cellular and synaptic level are not well understood. We found that the basal level of activin A, a member of the TGF-β family, which regulates hippocampal circuits in a behaviorally relevant fashion, is much higher in dorsal than in ventral hippocampus. Using transgenic mice with a forebrain-specific disruption of activin receptor signaling, we identified the pronounced dorsal-ventral gradient of activin A as a major factor determining the distinct neurophysiologic signatures of dorsal and ventral hippocampus, ranging from pyramidal cell firing, tuning of frequency-dependent synaptic facilitation, to long-term potentiation (LTP), long-term depression (LTD), and de-potentiation. Thus, the strong activin A tone in dorsal hippocampus appears crucial to establish cellular and synaptic phenotypes that are tailored specifically to the respective network operations in dorsal and ventral hippocampus.
Rutin co-treatment prevented cognitive impairment/depression-like behavior and decreased IDO activation following 35 days of ethanol administration in male Wistar rats
2023, Alcohol
Alcohol (ethanol) is among the most popularly consumed beverages globally. Ethanol was earlier demonstrated to elicit cognitive impairment and depressive-like effects in both human and animal studies. Rutin (R) is known for its antioxidant, anti-inflammatory, immunomodulatory, and anti-depressive properties, among others. Herein, we investigate the impact of rutin on ethanol-induced cognitive impairment and depressive-like effects in rats and the involvement of the indoleaminergic pathway. Three groups of eight rats each were orally exposed to drinking water (group 1), ethanol (5 g/kg body weight)-group 2 (via oral gavage), and ethanol + R (5 g/kg body weight + 50 mg/kg body weight)-group 3 (via oral gavage) for 35 days. Results showed that exposure to ethanol significantly (p < 0.0001) reduced spontaneous alternation in the Y-maze and increased immobility time in the tail suspension test (TST), which indicates cognitive impairment and depressive-like behavior in rats. We observed increased IDO activity/expression, and inflammatory responses, with attendant disruption in antioxidant systems and concomitant elevation in malondialdehyde (MDA) levels in the cerebral cortex and hippocampus. Following rutin co-exposure, an ethanol-mediated increase in indoleamine 2,3-dioxygenase [IDO] activity/expression and decrease in antioxidant enzymes, in addition to an increase in markers of inflammatory response and MDA production, was significantly (p < 0.0001) prevented compared with controls. Additionally, altered behavioral indices were prevented by rutin co-exposure. Taken together, these findings reveal the involvement of the indoleaminergic pathway in rutin preventive influence against ethanol-induced cognitive impairment and depressive-like behavior in rats.
Phytoestrogen genistein modulates neuron–microglia signaling in a mouse model of chronic social defeat stress
2022, Neuropharmacology
Microglia, resident immune cells in the brain, are shown to mediate the crosstalk between psychological stress and depression. Interestingly, increasing evidence indicates that sex hormones, particularly estrogen, are involved in the regulation of immune system. In this study, we aimed to understand the potential effects of chronic social defeat stress (CSDS) and genistein (GEN), an estrogenic compound of the plant origin, on neuron–microglia interactions in the mouse hippocampus. The time spent in the avoidance zone in the social interaction test was increased by CSDS 1 day after the exposure, while the avoidance behavior returned to control levels 14 days after the CSDS exposure. Similar results were obtained from the elevated plus-maze test. However, the immobility time in the forced swim test was increased by CSDS 14 days after the exposure, and the depression-related behavior was in part alleviated by GEN. The numerical densities of microglia in the hippocampus were increased by CSDS, and they were decreased by GEN. The voxel densities of synaptic structures and synaptic puncta colocalized with microglia were decreased by CSDS, and they were increased by GEN. Neither CSDS nor GEN affected the gene expressions of major pro-inflammatory cytokines. Conversely, the expression levels of genes related to neurotrophic factors were decreased by CSDS, and they were partially reversed by GEN. These findings show that GEN may in part alleviate stress-related symptoms, and the effects of GEN may be associated with the modulation of neuron–microglia signaling via chemokines and neurotrophic factors in the hippocampus.
TGF-β-Induced Phosphorylation of Usp9X Stabilizes Ankyrin-G and Regulates Dendritic Spine Development and Maintenance
2020, Cell Reports
Signaling by the cytokine transforming growth factor β (TGF-β) has been implicated in a multitude of biological functions; however, TGF-β signaling, particularly in the CNS, remains largely unexplored. ANK3 variants (encoding ankyrin-G) are associated with bipolar disorder, intellectual disability, and autism spectrum disorder, while mutations in USP9X, which encodes a deubiquitinase, are associated with X-linked intellectual disability and autism in humans. Here, we show that TGF-β signaling promotes Usp9X phosphorylation, which enhances its interaction with ankyrin-G and stabilizes ankyrin-G in spines, leading to spine enlargement. Using in situ proximity ligation combined with structured illumination superresolution microscopy, we characterize the postsynaptic spatial organization of phosphorylation-dependent regulation of Usp9X/ankyrin-G interactions in dendrites and its quantitative relationship with spine morphology and number. These data reveal a cytokine-mediated mechanism regulating protein stability in spines and suggest a role for deubiquitination and TGF-β signaling in neurodevelopmental disorder pathogenesis and treatment.
Renshen Shouwu extract enhances neurogenesis and angiogenesis via inhibition of TLR4/NF-κB/NLRP3 signaling pathway following ischemic stroke in rats
2020, Journal of Ethnopharmacology
Citation Excerpt :
Intriguingly, RSSW could increase MVD via angiogenesis in penumbra area following cerebral ischemic injury, further providing nutritive blood flow and favorable microenvironment for neurogenesis (Fig. 4). Emerging studies emphasize that IL-1β is involved in inhibiting the process of neurogenesis (Dowlati et al., 2010; Krieglstein et al., 2011; Pisanu et al., 2014). Moreover, neurological deficits caused by inflammatory responses are closely related to release of some endogenous ligands, which perform functions via Toll-like receptors (TLRs).
Renshen Shouwu extract (RSSW) is a patented Traditional Chinese Medicine included in Chinese Pharmacopoeia for neurasthenia, forgetfulness, insomnia, inappetence and excessive fatigue. Our previous study had demonstrated the neuroprotective effect of RSSW against ischemic stroke in rats with middle cerebral artery occlusion (MCAO). However, its underlying mechanism remains unknown.
In this study, we investigated the neurogenesis and angiogenesis effects of RSSW in ischemic stroke rats, and further revealed its underlying mechanism focused on TLR4/NF-κB/NLRP3 signaling pathway.
Firstly, active compounds of RSSW were determined by High Performance Liquid Chromatography (HPLC). Secondly, Middle cerebral artery occlusion (MCAO) was performed to induce ischemic stroke in rats and 2, 3, 5-Triphenyltetrazolium chloride (TTC) staining was employed to evaluate whether MCAO surgery was successfully established. Neurological deficit evaluation was conducted according to the Zea Longa’ method. Then, we explored the neurogenesis and angiogenesis effects after oral administration of RSSW (50 mg/kg, 100 mg/kg) in MCAO-induced rats by Immunofluorescence Staining. Moreover, the proteins involved in TLR4/NF-κB/NLRP3 signaling pathway (TLR4, p–NF–κB p65, NF-κB p65, NLRP3, pro-IL-1β, IL-1β, pro-Caspase-1, Caspase-1) were determined by western blotting.
It was observed that RSSW treatment significantly increased the number of newborn neurons and brain microvessel density (MVD) after ischemic stroke. What's more, RSSW treatment significantly downregulated TLR4, p–NF–κB p65/p65, NLRP3, pro-IL-1β, IL-1β, pro-Caspase-1, Caspase-1 proteins involved in TLR4/NF-κB/NLRP3 signaling pathway.
RSSW enhances neurogenesis and angiogenesis via inhibition of TLR4/NF-κB/NLRP3 inflammatory signaling pathway following ischemic stroke in rats. Hence, RSSW may be a promising Chinese Medicine for the treatment of ischemic stroke.
The cytokine network in the pathogenesis of major depressive disorder. Close to translation?
2020, Autoimmunity Reviews
Major depressive disorder (MDD) is a common condition that afflicts the general population across a broad spectrum of ages and social backgrounds. MDD has been identified by the World Health Organization as a leading cause of disability worldwide.
Approximately 30% of patients are poor responsive to standard of care (SOC) treatment and novel therapeutic approaches are warranted.
Since chronic inflammation, as it is often observed in certain cancers, type 2 diabetes, psoriasis and chronic arthritis, are accompanied by depression, it has been suggested that immunoinflammatory processes may be involved in the pathogenesis of MDD.
Cytokines are a group of glycoproteins secreted from lymphoid and non-lymphoid cells that orchestrate immune responses. It has been suggested that a dysregulated production of cytokines may be implicated in the pathogenesis and maintenance of MDD. On the basis of their functions, cytokines can be subdivided in pro-inflammatory and anti-inflammatory cytokines. Since abnormal blood and cerebrospinal fluid of both pro and anti-inflammatory cytokines are altered in MDD, it has been suggested that abnormal cytokine homeostasis may be implicated in the pathogenesis of MDD and possibly to induction of therapeutic resistance.
We review current data that indicate that cytokines may represent a useful tool to identify MDD patients that may benefit from tailored immunotherapeutic approaches and may represent a potential tailored therapeutic target.

View all citing articles on Scopus

View full text

Trends in Neurosciences

ReviewMore than being protective: functional roles for TGF-β/activin signaling pathways at central synapses

Introduction

Section snippets

The TGF-β family and associated signaling pathways

TGF-β

TGF-β

Tuning synapses versus protecting neurons

Conclusions

Acknowledgments

Cytokine Growth Factor Rev.

Curr. Biol.

Curr. Opin. Neurobiol.

J. Endocrinol.

Neuroscience

Int. J. Dev. Neurosci.

J. Biol. Chem.

Brain Res.

Cell

Curr. Opin. Cell Biol.

Kidney Int.

Curr. Biol.

Curr. Opin. Cell Biol.

Neuron

Neuron

Neuron

Neuron

Prog. Brain Res.

Neuron

Neuroscience

J. Biol. Chem.

Brain Res.

Neurosci. Lett.

Mol. Cell Neurosci.

Neuroscience

FEBS Lett.

J. Biol. Chem.

Neuroscience

Cell

Lab. Invest.

Trends Endocrinol. Metab.

Cytokine Growth Factor Rev.

Cell

J. Mol. Cell Cardiol.

Brain Res.

Neuroscience

Exp. Neurol.

Dorsal–ventral patterning and neural induction in Xenopus embryos

Annu. Rev. Cell Dev. Biol.

The Decapentaplegic morphogen gradient: from pattern formation to growth regulation

Nat. Rev. Genet.

Differentiation plasticity regulated by TGF-beta family proteins in development and disease

Nat. Cell Biol.

TGF-beta and the TGF-beta family

Wnts and TGF beta in synaptogenesis: old friends signalling at new places

Nat. Rev. Neurosci.

Bone morphogenetic proteins and their receptors: potential functions in the brain

J. Neurosci. Res.

Expression of serine/threonine kinase receptors including the bone morphogenetic factor type II receptor in the developing and adult rat brain

Cell Tissue Res.

Spatiotemporal expression patterns of mammalian chordin during postgastrulation embryogenesis and in postnatal brain

Dev. Dyn.

Extracellular control of TGFbeta signalling in vascular development and disease

Nat. Rev. Mol. Cell Biol.

The regulation of TGFbeta signal transduction

Development

Two major Smad pathways in TGF-beta superfamily signalling

Genes Cells

Activins and inhibins

Pituitary actions of ligands of the TGF-beta family: activins and inhibins

Reproduction

Review
More than being protective: functional roles for TGF-β/activin signaling pathways at central synapses