regulation of neural process growth, elaboration and structural plasticity by nf-κb

Review

Regulation of neural process growth,elaboration and structural plasticity byNF-kBHumberto Gutierrez* and Alun M. Davies

Cardiff School of Biosciences, University of Cardiff, Biomedical Sciences Building 3, Cardiff CF10 3AT, UK

The nuclear factor-kappa B (NF-kB) family of transcriptionfactors has recently emerged as a major regulator of thegrowth and elaboration of neural processes. NF-kB sig-naling has been implicated in controlling axon initiation,elongation, guidance and branching and in regulatingdendrite arbor size and complexity during developmentand dendritic spine density in the adult. NF-kB is activatedby a variety of extracellular signals, and either promotesor inhibits growth depending on the phosphorylationstatus of the p65 NF-kB subunit. These novel rolesfor NF-kB, together with recent evidence implicatingNF-kB in the regulation of neurogenesis in the embryoand adult, have important implications for neural devel-opment and for learning and memory in the maturenervous system.

IntroductionThe nuclear factor-kappa B (NF-kB) family of transcriptionfactors is ubiquitously expressed, but it has been studiedmost extensively in themammalian immune systemwhereit plays a key role in regulating the expression of genesinvolved in innate and adaptive immune responses, in-flammatory responses, cell survival and cell proliferation[1]. NF-kB proteins are widely expressed in the developingandmature nervous system, and studies of NF-kB reportermice have revealed NF-kB activity in multiple brainregions at various stages of development and in the adult[2,3]. A wide variety of extracellular signals regulate NF-kB activity in the nervous system including neurotrans-mitters, neuropeptides, neurotrophins, cytokines and neu-ral cell adhesionmolecules (NCAMs) [2,4]. NF-kB has beenimplicated in regulating the expression of an increasingnumber of genes involved in neural development and/orfunction, for example, those encoding the NCAM [5] andreceptors for some neurotransmitters, neuropeptides andneurotrophic factors [6–10]. NF-kB signaling is involved inseveral aspects of neural development including the regu-lation of neurogenesis in the embryo and adult [11–14], theregulation of cell survival in certain populations of periph-eral and central neurons [2,15] and in promoting periph-eral nerve myelination [16,17]. In the mature nervoussystem, a substantial body of evidence has implicatedNF-kB signaling in diverse aspects of learning andmemory

Corresponding author: Davies, A.M. ([email protected])* Current address: Instituto de Fisiologıa Celular, Universidad Nacional Autonoma

de Mexico, Ciudad Univesitaria, Mexico D.F., Mexico.

316 0166-2236/$ – see front matter � 2011 Elsevier Ltd. All rights res

[3,4]. Furthermore, inducible NF-kB participates in thecellular responses to neuronal insult and neurologicaldiseases with beneficial or detrimental consequences.For example, in a variety of in vitro and in vivo models,NF-kB has been shown to have a neuroprotective functionin apoptosis induced by glutamate, kainate, oxidativestress and amyloid b peptide [18]. Conversely, NF-kBhas been implicated in enhancing neuronal apoptosis as-sociated with ischemic brain injury, neurodegenerativediseases and inflammatory conditions [19].

In this review, we discuss emerging evidence for a majornew role for NF-kB in regulating the growth and morphol-ogy of neural processes. After introducing the NF-kB fami-ly and the basics of NF-kB signaling, we provide an in-depth analysis of the ways in which NF-kB affects theelaboration and structural modification of neural process-es. Furthermore, we discuss the broader significance ofthese findings and other recent advances with respect tothe neurodevelopmental roles of NF-kB and its importancein learning and memory.

The NF-kB family and NF-kB signaling pathwaysIn mammals, the NF-kB family of transcription factorsconsists of five structurally related proteins, p65, RelB, c-Rel, p50 and p52, that form homodimers and heterodimersthat induce or repress gene expression by binding to DNAsequences (kB elements) within the promoters and enhan-cers of target genes [20]. NF-kB dimers are held in aninactive form in the cytosol by interactionwith amember ofthe IkB family of proteins (see Box 1). NF-kB is activated byremoval of the inhibitory IkB protein and translocation ofthe liberated NF-kB dimer to the nucleus. The predomi-nant transcriptionally active form of NF-kB in the nervoussystem is the p65/p50 heterodimer whereas IkBa is themost common inhibitor.

A great variety of stimuli activate NF-kB in different celltypes via several distinct pathways (Figure 1). In the canon-ical NF-kB signaling pathway, NF-kB is activated by phos-phorylation of IkBa on Ser32 and Ser36 by the IkB kinase-b(IKKb) catalytic subunit of an IkB kinase (IKK) complexthat consists of IKKb together with another catalytic sub-unit, IKKa and a regulatory subunit IKKg. This leads toubiquitylation and proteasome-mediated degradation ofIkBa and translocation of the liberated NF-kB dimer tothe nucleus [20]. In the non-canonical NF-kB signalingpathway, the p100 subunit of p100–RelB heterodimers is

erved. doi:10.1016/j.tins.2011.03.001 Trends in Neurosciences, June 2011, Vol. 34, No. 6

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http://dx.doi.org/10.1016/j.tins.2011.03.001

Box 1. NF-kB and IkB families

The members of the mammalian NF-kB family, p65 (also known as

RelA), RelB, c-Rel, p50 and p52, together with the p100 and p105

precursors of p52 and p50, share a conserved, multifunctional Rel

homology domain (RHD) of approximately 300 amino acids that

mediates dimerization, IkB protein binding and DNA binding

(Figure I). The RHD contains a nuclear localization sequence that

is masked by bound IkB protein and promotes nuclear translocation

following IkB removal. p65, RelB and c-Rel additionally possess

unrelated C-terminal transactivational domains (TAD), RelB has a

leucine zipper (LZ), p52, p50 and their precursors have glycine-rich

regions (GRR) and the latter precursors additionally possess

regions with homology to death domains (DD). Phosphorylation

of p65 at S536 switches activated NF-kB from a promoter to an

inhibitor of neurite growth.

IkB proteins include p100, p105, IkBa, IkBb, IkBe, IkBg and Bcl-3.

They contain several ankyrin-repeat motifs (denoted by green ovals)

that mediate binding to RHDs. The ankyrin-repeat motifs in the C-

terminal regions of the p105 and p100 act as auto-inhibitory IkB-like

domains, retaining these precursors and their partner NF-kB proteins

in the cytoplasm. Various phosphorylation sites (S32, S36 and Y42)

within IkBa have been demonstrated to be important in regulating

NF-kB activation. In contrast to the other IkB proteins, B-cell

lymphoma-3 (BCL-3) is a nuclear protein that functions as a

transcriptional co-activator.[()TD$FIG]

NF-κB family S536

p65(Rel A)

551 aa RHD TAD

P

Rel B 557 aa RHD TAD LZ

c-Rel 619 aa RHD TAD

p52 447 aa RHD

p50 430 aa

GRR

RHD GRR

p105(p50 precursor)

971 aa RHD GRR DD

898 aa RHD GRR DD p100(p52 precursor)

IκBα 317 aa

IκBβ 361 aa

500 aa

IκBγ 607 aa

Bcl-3 446 aa

S32 P P P

S36 Y42

IκB family

IκBε

TRENDS in Neurosciences

Figure I. Schematic diagram illustrating the mammalian members of the NF-kB and IkB families.

Review Trends in Neurosciences June 2011, Vol. 34, No. 6

phosphorylated by the IKKa subunit of the IKK complex,which results in ubiquitylation and proteosome-dependentprocessing of p100 to p52, followed by translocation of theresulting p52–RelB dimers to the nucleus. An additionalIKK-independent NF-kB activation mechanism has beendescribed in which IkBa is phosphorylated on Tyr 42, whichresults indissociationof IkBa fromNF-kBand translocationof NF-kB to the nucleus. We will refer to this NF-kB activa-tion mechanism as tyrosine kinase-dependent (TK-depen-dent) NF-kB signaling.

The function of nuclear NF-kB is controlled by numer-ous post-translational changes to the NF-kB subunits,including phosphorylation and acetylation on specific resi-dues that can affect transcriptional activity, target genespecificity or termination of the NF-kB response [21]. Inaddition to being modified and functionally modulated byother signaling pathways, components of the NF-kB sig-naling system affect the function of many other signalingproteins and transcription factor systems in the cell. IKKa

and IKKb, in particular, phosphorylate a wide variety of

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[()TD$FIG]

CNTF

CNTFreceptorcomplex

SYK

BDNF

TrkB

Src/Lck

IκBα

P

Y42

TNFR1

TNFα

IκBα

S32/S36 P P

S536

p50 p65

P

p50 p65

p50 p50 p65

κB site

Axonal growthinhibition

Gene transcription

κB site

Canonical pathway TK-dependent activation

Nodose neurons Sympathetic neurons

Cyt

opla

sm

Gene transcriptionGene transcription Gene transcription

Nuc

leus

IKKγ

Nodose neurons(constitutive activation)

IκBα

S32/S36

P P

p50

Enhanced axonalgrowth

κB site

Enhanced axonalgrowth

Enhanced dendriticgrowth

NGF

p75

κB site

Hippocampal neurons

PTPB1

Src

IκBα

P

Y42

p50 p65

p50 p65 P

Proteosome- mediated

degradation

IκBα

P Y42

Dissociationof IκBα

Proteosome- mediated

degradation

(a) (b) (c) (d) TK-dependent activation Canonical pathway

p65

IKKαIKKβ

TRADD

RIP TRAF2/5

p50 p65

p65


Figure 1. NF-kB signaling pathways regulating neurite growth from cultured neurons.

In the canonical pathway (a,b), activated IKKb phosphorylates (P) IkBa at Ser32 and Ser36, leading to its ubiquitination and degradation by the proteasome, allowing the

released p65/p50 dimer to translocate to the nucleus. IKKb can also phosphorylate p65 at the Ser 536 residue, which switches NF-kB to a neurite growth-inhibitory function.

Of the many extracellular signals that activate the canonical pathway, TNFa binding to tumor necrosis factor receptor-1 (TNFR1) is among the most extensively studied [1]

and is known to operate in sympathetic neurons with resultant p65 phosphorylation and axonal growth inhibition (a) [37]. TNFR1 ligation results in receptor trimerization

and the recruitment of several adapter proteins (TNFR1-associated death domain protein, TRADD; receptor interacting protein 1, RIP1; TNFR-associated factors, TRAF2 and

TRAF5) and the IKK complex, which results in IKKb phosphorylation by the participation of additional proteins recruited to the signaling complex (not shown). Canonical

signaling without significant levels of phospho-S536–p65 facilitates BDNF-promoted axonal growth from nodose ganglion neurons during an E18–P1 developmental

window (b) [33], although the upstream activators of this pathway have yet to be identified. In the TK-dependent pathway (c,d), IkBa is phosphorylated at Tyr42, resulting in

its dissociation (with or without degradation) from the p65/p50 dimer and translocation of the latter to the nucleus, and subsequent enhancement of neurite growth. In

nodose ganglion sensory neurons (c), binding of BDNF to TrkB during an E15 to E17 developmental window results in phosphorylation of IkBa by Src and Lrk [35], whereas

CNTF signaling during perinatal development activates the tyrosine kinase SYK, which in turn phosphorylates IkBa, leading to its removal without proteasome-dependent

degradation [34]. In hippocampal neurons (d), binding of NGF to the p75NTR receptor results in PTPB1-dependent phosphorylation of IkBa by the tyrosine kinase Src [53].


substrates in many other signaling pathways, and there-fore have wide-ranging effects on cellular function [21].

Regulation of the growth and morphology of neuralprocessesThe growth, branching and spatial arrangement of axonsand dendrites in the developing nervous system is regulat-ed by amultitude of extracellular proteins and by changingpatterns of neural activity as neurons establish andmodifysynaptic connections [22,23]. Extracellular signals andneural activity trigger changes in intracellular signalingnetworks that control the assembly and organization of the

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growth cone cytoskeleton and engage transcription factorsthat modulate the expression of genes required for growth.Extensive work over the past two decades has demonstrat-ed the participation of several pivotal intracellular signal-ing proteins and transcription factors in the regulation ofaxon and dendrite growth, including phosphatidylinositol-3 kinase, glycogen synthase kinase 3, calcium/calmodulin-dependent protein kinases (CaMKs), mitogen activatedkinases, cyclic AMP response element binding protein(CREB) and nuclear factors of activated T-cells [24].

Dendritic spines, the small protrusions that are the siteof most of the excitatory synapses on principal neurons of

Table 1. Influence of NF-kB signaling on the generation and morphological differentiation of neurons

NF-kB-regulated cellular function Cell type and stage of development Refs

Neurogenesis � Embryonic NSCs [11,80]

� Adult NSCs [12–14,82,83]

Cell differentiation � Differentiation of proliferating PC12 cells

into neuron-like cells

[39–41,43,44]

Axon initiation � Embryonic hippocampal neurons [46]

Axon guidance � Drosophila photoreceptor axons [51]

Axon growth and branching � Perinatal nodose ganglion sensory neurons [33–36]

Inhibition of axon growth and branching � TNFa inhibition of NGF-promoted axon

growth from perinatal sympathetic neurons

[37]

Dendritic growth and branching � Postnatal cortical pyramidal neurons [33]

� Embryonic hippocampal neurons [52–55]

� Postnatal cerebellar Purkinje cells [57]

Dendritic spine number and morphology � Adult NAc medium spiny neurons [58,59]


the central nervous system (CNS), rapidly accumulatewith the growth and elaboration of dendritic arbors [25].These dynamic structures are turned over at a relativelyhigh rate during development with a net gain in numberinto early postnatal development, after which substantialnumbers are lost. Although spine number remains rela-tively constant during adulthood and the great majority ofspines are long lasting and underpin long-term informa-tion storage [26], spine turnover continues at a low ratethroughout life [25]. Dendritic spines also exhibit rapid,activity-dependent changes in size and shape [27]. Forexample, the dendritic spines of hippocampal pyramidalneurons increase in volume during long-term potentiation(LTP) and shrink during long-term depression (LTD) [28].Although LTD can occur without obvious structuralchanges in spines [29], activity-dependent structural plas-ticity in dendritic spines is thought to contribute to changesin synaptic strength [27]. These findings together with thedemonstration that changes in sensory experience can leadto persistent changes in spine density [28,30] and thatinstructive experiences lead to spine stabilization andenlargement [31,32] have strongly implicated structuralspine plasticity in learning and memory.

In the following sections, we describe recent work thatimplicates NF-kB as a major player in the intracellularsignaling and transcriptional networks that regulate thegrowth and elaboration of axons and dendrites during de-velopment (Table 1). Thiswork, togetherwith recent reportsimplicating NF-kB signaling in the regulation of dendriticspine density, are subsequently discussed in the context ofthe broader significance of NF-kB in learning and memory.

NF-kB in the regulation of axon growth and branchingEvidence for the regulation of axonal growth by NF-kB hascome from studying the effects of manipulating NF-kBsignaling pathways in primary cultures of nodose ganglionsensory neurons established from developing mice(Figure 2a). These neurons survive and extend longbranching axons on laminin-coated culture dishes in me-dium containing either brain-derived neurotrophic factor(BDNF) or ciliary neurotrophic factor (CNTF). From aseries of detailed developmental studies of these neurons[33–36], a complex picture has emerged in which the NF-kB signaling pathway affecting axon growth and its mech-anism of activation depends on the developmental stage of

these neurons and the neurotrophic factor used to supporttheir survival.

Although NF-kB signaling makes a major contributionto BDNF-promoted neurite growth throughout late fetaland early postnatal development, shortly before birththere is an abrupt switch in the NF-kB signaling networkrequired for BDNF-promoted neurite growth. During anarrow developmental window between embryonic day15 (E15) and E17, BDNF strongly activates the TK-depen-dent NF-kB signaling pathway through activation of itsreceptor TrkB and subsequent activation of two membersof the Src family of tyrosine kinases, Src and Lck. Thesekinases in turn phosphorylate IkBa on Tyr 42 [35](Figure 1c). Blocking the TK-dependent NF-kB signalingpathway, but not the canonical signaling pathway, duringthis window of development significantly reduces BDNF-promoted axon growth and branching [35].

Subsequently, during a narrow developmental windowbetween E18 and postnatal day 1 (P1), blocking the canon-ical signaling pathway, but not the TK-dependent NF-kBsignaling pathway, significantly reduces BDNF-promotedaxon growth and branching [33]. BDNF does not activateNF-kB signaling during this latter period of development,and the mechanism by which NF-kB transcriptional activ-ity is maintained in nodose neurons during this period isnot yet understood [33] (Figure 1b). The relatively high invivo levels of phospho-Tyr42-IkBa in late fetal nodoseganglia and the subsequent marked decrease in the levelof IkBa phosphorylated at Tyr42 residue during the earlypostnatal period is consistent with the in vivo operation ofthe TK-dependent NF-kB activation mechanism prenatal-ly and its subsequent loss postnatally [35]. The reason forthe switch and developmental plasticity in the NF-kBsignaling network required for BDNF-promoted axongrowth is unclear, but it may be necessary to facilitateother physiological or developmental changes occurring inthe neurons over this period. Interestingly, tumor necrosisfactor superfamily member 14 (TNFSF14/LIGHT) actingvia its receptor TNFRSF14/HVEM is a potent inhibitor ofNF-kB signaling and negative regulator of BDNF-promot-ed neurite growth from nodose neurons during the E18–P1developmental window [36].

Like BDNF, CNTF also activates the TK-dependentNF-kB signaling pathway in developing nodose neurons[34], but unlike BDNF, which activates NF-kB only during

319

[()TD$FIG]

IκBα IκBαIκBα

Controltransfection

S32/S36

P P

Nodose sensory neurons (a)

Controltransfection P

Y42

Hippocampal neurons (c)

NGF NGF + Y42F IκBα

S32/S36

P P Controltransfection

Cortical pyramidal neurons (b)

Control

BDNF + S32A/S36A IκBα BDNF

S32A/S36A IκBα


Figure 2. Effects of selectively inhibiting NF-kB signaling pathways on axon and dendrite growth and morphology. Examples of selectively inhibiting the canonical

signaling pathway in dissociated cultures of (a) dissociated nodose ganglion neurons cultured with BDNF and (b) pyramidal neurons in somatosensory cortical slice

cultures by ballistic transfection with a plasmid expressing a super-repressor S32A/S36A IkBa. In the slice cultures, S32A/S36A IkBa-transfected and control-transfected

neurons were identified in the same preparation by co-transfection with plasmids expressing green and red florescent proteins, respectively. Inhibition of NF-kB canonical

signaling significantly reduced the size and complexity of the respective axon and dendrite arbors of these sensory and pyramidal neurons. (c) Examples of dissociated

hippocampal neurons cultured with NGF and transfected with control and Y42F–IkBa-expressing plasmids to selectively inhibit the TK-dependent activation pathway.

Inhibition of this pathway resulted in an increase in the number of primary dendrites and a reduction in dendrite elongation. Reproduced, with permission, from [33] (panels

a and b) and [54] (panel c).


a narrow window of late fetal development, CNTF potentlyactivates NF-kB in both fetal and postnatal neurons [35].CNTF treatment activates spleen tyrosine kinase (SYK),which in turn phosphorylates IkBa on Tyr 42, leading toincreased NF-kB transcriptional activity. Blocking eitherSYK activation or the TK-dependent NF-kB signalingpathway, but not the canonical signaling pathway, virtu-ally eliminates CNTF-promoted axonal growth, demon-strating a crucial requirement for NF-kB signaling inaxonal growth in response to this neurotrophic factor[34] (Figure 1c). Taken together, the above studies ondeveloping sensory neurons indicate that different extra-cellular regulators of axon growth converge on the NF-kBsignaling network in various ways at different stages indevelopment to enhance axon growth and branching.

In addition to enhancing growth, NF-kB signaling canalso exert a potent inhibitory effect on axon growth. Wheth-er NF-kB promotes or inhibits growth depends on themechanismofNF-kBactivation and the resultingphosphor-ylation status of the p65 NF-kB subunit. Neonatal sympa-thetic neurons, which survive and extend axons in responseto the neurotrophin nerve growth factor (NGF), contain p65that is constitutively phosphorylated on Ser 536 (phospho-S536–p65). Inhibiting NF-kB transcriptional activity inthese neurons does not affect NGF-promoted neuritegrowth, and enhancing NF-kB transcriptional activity by

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tumor necrosis factor a (TNFa) treatment or by overexpres-sing p65, p65/p50, or IKKb strongly inhibits NGF-promotedneurite growth [37] (Figure 1a). By contrast, neonatal no-dose neurons contain barely detectable levels of phospho-S536-p65 protein, and inhibiting NF-kB transcriptionalactivity in these neurons reduces BDNF-promoted neuritegrowth, whereas enhancing NF-kB transcriptional activityby overexpressing p65/p50 increases neurite growth [37].However, enhancing NF-kB transcriptional activity in no-dose neurons by overexpressing IKKb, which additionallyphosphorylates p65 on Ser 536, strongly inhibits BDNF-promoted neurite growth [37]. The demonstration that anS536D–p65 phosphomimetic mutant also inhibits neuritegrowth in nodose neurons and that blockade of Ser 536phosphorylation by a S536A–p65 mutant protein preventsthe growth inhibitory effects of IKKb overexpression in bothnodose and sympathetic neurons indicate that the phos-phorylation of p65 on Ser 536 is a key determinant ofwhether NF-kB signaling promotes or inhibits neuritegrowth [37]. Interestingly, BDNF treatment of fetalnodose neurons between E15 and E17 not only activatesTK-dependent NF-kB signaling but also promotes dephos-phorylation of p65 on S536, both of which facilitate axonextension [35]. Although the molecular mechanism bywhich the phosphorylation status of p65 affects axon growthis unknown, it seems likely that phosphorylated S536–p65


and non-phosphorylated S536–p65 regulate different sets ofgenes that have opposing effects on axon growth. Ser 536 islocated within a C-terminal transactivation domain of p65,and there is evidence that the phosphorylation status ofS536 in p65 differentially affects which sets of genes will betranscribed [38].

Although inhibiting NF-kB activity in neonatal sympa-thetic neurons does not affect NGF-promoted neuritegrowth [37], in the PC12 pheochromocytoma cell line,which responds to NGF by exiting the cell cycle anddifferentiating into sympathetic neuron-like cells, inhibit-ing NF-kB signaling impairs differentiation into cells withshort neurite-like processes [39–41]. NGF activates NF-kBsignaling in PC12 cells [42], and enhancing NF-kB signal-ing in these cells in the absence of NGF by overexpressingNF-kB inducing kinase, an upstream activator of IKKa, orby expression of a constitutively active form of IKKb

increases the percentage of neurite-bearing cells [43,44].In contrast to PC12 cells, normal sympathetic neuroblastsexit the cell cycle and differentiate into neurons indepen-dently of NGF and only become responsive to this neuro-trophin after their axons reach their targets in vivo [45].Nonetheless, these intriguing findings in PC12 cells raisethe possibility that NF-kB signaling may play some role inregulating the differentiation of sympathetic neuroblastsand/or promoting the growth of neurites from neuroblastsand early sympathetic neurons. For these reasons, it willbe informative to explore the effects of manipulating NF-kB signaling on proliferation, differentiation and de novoneurite growth in primary cultures of sympathetic neuro-blasts and early post-mitotic sympathetic neurons.

In addition to regulating the growth of sensory andsympathetic axons during the stage of development whenthey are growing and branching extensively under theinfluence of target-derived neurotrophins, NF-kB signalinghas recently been implicated in the earlier stages of axoninitiation and guidance. In cultures of E17 mouse hippo-campal neurons, phospho-S32/36–IkBa is selectively dis-tributed along the length of early axons and becomesprogressively concentrated in the axon initial segment(AIS) with axon elongation [46]. Phospho-IKKb is presentin these early neurons, and pharmacological inhibition ofIKK significantly reduces the level of phospho-IkBa andsignificantly impairs axon formation without affecting thedevelopment of minor neurites [46]. Phospho-IkBa immu-noreactivity in the AIS of hippocampal and cortical neu-rons increases from prenatal to postnatal stages [46].Furthermore, phospho-IkBa, activated IKK and phos-pho-S536–p65 are expressed in the AIS of a wide varietyof neurons in other adult rat CNS regions [47], raising thepossibility that NF-kB signaling might play a role inaxogenesis of many different neuronal subtypes. Whetheractivated IKK and/or phospho-IkBa promote AIS specifi-cation and/or early axon extension in developing hippo-campal neurons by a local effect on the cytoskeleton and/orby retrograde NF-kB signaling to the nucleus with changesin gene expression is unclear. IKK, for example, regulatesF-actin assembly [48] and b-catenin stability [49], andb-catenin has been implicated in axon initiation [50]. Evi-dence for a role for NF-kB signaling in axon guidance hascome from the observation thatmisexpression of Dorsal, an

NF-kB protein in Drosophila, causes photoreceptor axonsto reach incorrect positions within the optic lobe [51].

NF-kB in the regulation of dendritic growth andmorphologySeveral studies have demonstrated a role for NF-kB sig-naling in regulating the growth and morphology of den-dritic arbors in several regions of the developing andmature CNS. In the intact neuropil of somatosensorycortical slice cultures prepared from P3/P4mice, inhibitingeither NF-kB canonical signaling or NF-kB-mediated tran-scriptional activation causes highly significant reductionsin dendritic length and branching of layer 2/3 pyramidalneurons [33] (Figure 2b). Pharmacological inhibition ofIKK in E17 dissociated rat hippocampal neurons alsosignificantly reduces dendritic length and branching[52]. A particularly thorough and detailed series of studiesin E17 dissociated mouse hippocampal neurons hasrevealed a chain of molecular events linking neurotrophinstimulation to changes in dendrite growth via sequentialactivation of NF-kB and other transcription factors. In low-density cultures, NGF reduces the number of primarydendrites and promotes dendrite elongation by bindingto the common neurotrophin receptor (p75NTR) [53](Figure 2c). This leads, by an unknown mechanism, tothe activation of protein tyrosine phosphatase 1B, whichactivates protein tyrosine kinases, including Src, thatphosphorylate Tyr42 of IkBa, resulting in NF-kB activa-tion [54] (Figure 1d). Selectively inhibiting TK-dependentNF-kB signaling, but not canonical signaling, inhibits theeffects of NGF on dendrite morphology in these cultures.

NF-kB-dependent enhanced expression of the helix-loop-helix transcription factors, Hes1 and Hes5, plays akey role in bringing about the effects of NGF on dendritenumber and growth [53]. These effects of NGF on dendritesare also partly dependent on NGF-promoted decrease inthe expression of the proneural basic helix-loop-helix tran-scription factors, neurogenin-3 and Mash1 [55]. BecauseHes proteins are repressors of proneural gene transcrip-tion [56], it is possible that NF-kB activation initiates atranscription factor cascade that mediates the effects ofneurotrophins on dendrite morphology. Interestingly,Notch signaling, which is also a key regulator of dendritegrowth, also regulates Hes1/5 expression. Indeed, Notchand two of its ligands, Delta-1 and Jagged-1, are expressedtogether with p75NTR and Hes1/5 in CA3 pyramidal neu-rons of the hippocampus [55], suggesting convergence ofNotch and neurotrophin-regulated NF-kB signaling in thecontrol of dendritic morphology, at least in this brainregion.

Evidence for the participation of NF-kB in dendritogen-esis in the developing cerebellum has come from analysis ofthePurkinje cell degenerationmutantmouse, psdSid, whichhas an exon 7 deletion in Nna1 and is characterized byunderdevelopment of Purkinje cell dendrites [57]. ThePurkinje cells of these mice have reduced expression andnuclear localization of p65 both in vivo and in vitro. Knock-down of p65 by short hairpin RNA (shRNA) in developingwild type Purkinje cells in culture mimics the detrimentaleffect of Nna1 knockdown on dendritic arbor sizeand complexity [57]. Moreover, p65 overexpression was

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observed to completely reverse the effects of Nna1 knock-down on dendrite growth [57].

It has recently been reported that manipulating thefunction of IKKb in medium spiny neurons (MSNs) of thenucleus accumbens (NAc) of adult mice in the context ofreward and stress behavioral paradigms influences dendrit-ic spine density and morphology [58,59]. Viral-mediatedtransfection of MSNs with a constitutively active IKKb

(caIKKb) mutant that activates NF-kB signaling was foundto increase the number of dendritic spines in these neuronswhereas a dominant-negative IKKb (dnIKKb) mutant de-creased spine number [58]. Chronic cocaine exposure alsoincreased spine number and induced NF-kB-dependenttranscription in the NAc. The demonstration that dnIKKb

blocked both the ability of cocaine to increase spine numberand its rewarding effects suggests that IKK participates inregulating the structural and behavioral plasticity thataccompanies chronic cocaine exposure [58]. Chronic socialdefeat stress has been shown to increase the levels of IKK,IkBandphospho-IkBproteins in theNAcand to increase thedensity of stubby-type spines in the MSNs of a subset ofanimals that respond to such stress with social avoidance[59]. The finding that the dnIKKb viral vector reverses boththe increased formation of stubby spines and social avoid-ance insusceptible animalsand that the caIKKbviral vectorpromotes social avoidance in mice subjected to a subthresh-old social defeat regime suggests that IKK plays a role inregulating stress-induced adaptive plasticity in the NAc[59]. It should be noted, however, although bicistronic her-pes simplex viral vectors were used to manipulate IKKfunction and identify IKK-transfected MSNs in both stud-ies, because these vectors infect a variety of cell types, it isuncertain whether the observed changes in spine densityand morphology resulted exclusively from interfering withIKK function inMSNs themselves. Furthermore, since IKKfunction affects a variety of signaling pathways in the cell inaddition to modulating NF-kB activation [20], because NF-kB transcriptional activation was not specifically blocked inthesestudies, it remains tobedetermined towhat extent theobserved changes indendritic spinedensity andmorphologyweremediated byNF-kB-regulated changes in gene expres-sion.

NF-kB transcriptional targets in the regulation of axonaland dendritic growthAlthough the available evidence suggests that the effects ofNF-kB signaling on the growth of neural processes arebrought about by NF-kB-dependent changes in gene tran-scription, the relevant transcriptional targets are largelyobscure. Only in the case of Purkinje dendritic growth havetwo of the required NF-kB transcriptional targets beenidentified, namely those encoding the microtubule-associ-ated proteins, MAP2 and MAP1B [57]. These proteins aremainly localized in the somatodendritic compartment ofneurons where they promote microtubule assembly andstabilization, and have been shown to play a key role indendrite elongation in developing hippocampal neurons[60,61]. The underdeveloped Purkinje dendrites of psdSid

mice exhibit reduced expression of MAP2 andMAP1B, andshRNA knockdown of these proteins in wild type cerebellarneurons also suppresses dendrite growth in culture [57].

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Knockdown of p65 in wild type cerebellar neurons resultsin reduced expression of MAP2 and MAP1B, and thedetrimental effect of p65 knockdown on dendrite growthis prevented by overexpressing MAP2 and MAP1B [57].Although these findings suggest that MAP2 and MAP1Bplay a role in mediating the effects of NF-kB signaling ondendrite growth, they do not reveal if additional NF-kB-regulated genes are required. Furthermore, these dendri-tically-localized proteins are unlikely to have any bearingon how NF-kB affects axonal growth.

Of themultitude of genes regulated by NF-kB in variouscell types, several encode proteins that have been impli-cated in cell adhesion and neurite growth, such as b1integrin [62], NCAM [5], slit and Trk-like family member1 and T-lymphoma and metastasis 1 [52]. NF-kB alsoregulates the expression of glial cell-derived neurotrophicfactor (GDNF) family receptor a1, which influences theresponsiveness of Neuro2a neuroblastoma cells to GDNF[9]. In addition to evaluating the importance of particularNF-kB transcriptional targets in mediating the effects ofNF-kB signaling on axon and dendrite growth, transcrip-tome profiling of neurons under experimental conditions inwhich NF-kB signaling either promotes or inhibits growthis likely to provide additional NF-kB transcriptional tar-gets that are candidates for mediating NF-kB-regulatedstructural plasticity.

Implications for learning and memory of the effects ofNF-kB on structural plasticity, neurogenesis and genetranscriptionNumerous pharmacological and genetic studies utilizing avariety of experimental paradigms have implicated NF-kBsignaling in learning and memory in diverse species. Forexample, pharmacological inhibition of NF-kB interfereswith memory formation in the crab [63], and administra-tion of NF-kB decoy DNA interferes with long-term fearmemory [64], long-term inhibitory avoidance memory [65]and long-term spatial memory [66] in rodents. Geneticevidence for the participation of NF-kB signaling in learn-ing and memory has come from the analysis of severalknockout, conditional knockout and conditional overex-pression mouse lines (for a review, see [3]). For example,p50�/� mice have a selective deficit in short-term spatialmemory performance [13], c-rel�/� mice have impairedhippocampus-dependent memory formation [67], anddefects in spatial learning have been observed in p65–/–/Tnfr1�/� mice [68] and CamKII-tTAtetOtn IkBa mice,which conditionally express the super-repressor IkBa inforebrain glutamatergic neurons [69]. Conversely, Prion-tTAtetOtn IkBa mice that conditionally express high levelsof the super-repressor IkBa in GABAergic neurons, and atlower levels in glutamatergic neurons, display increasedexploratory activity and enhanced spatial learning andmemory [70]. Whereas reduced LTP and LTD are evidentin CamKII-tTAtetOtn IkBa mice [69] and late-phase LTPis impaired in c-rel�/�mice [67], enhanced LTP is observedin Prion-tTAtetOtn IkBa mice [69].

Links between synaptic function and NF-kB signalingthat are potentially relevant for learning and memory havebeen increasingly recognized. The p65 and p50 NF-kB sub-units are detectable at pre- and postsynaptic sites in vivo


and in synaptosomes isolated from the cerebral cortex andhippocampus [68,71]. Glutamatergic stimulation of cul-tured cerebellar granule cells and hippocampal neurons,or isolated hippocampal synaptosomes, enhances NF-kBDNA binding activity, whereas pharmacological inhibitionof ionotropic glutamate receptors or L-type Ca2+ channelssuppresses basal NF-kB activity [68,72,73]. NF-kB is alsoactivated in themouse hippocampus by perforant path LTPin vivo [74]. Followingglutamatergic stimulation of culturedhippocampal neurons, NF-kB is conveyed from distal den-drites to the nucleus by active, dynein-dependent transport[66,75–77].Collectively, thesestudies indicate thatNF-kBiscapable of transducing changes in synaptic activity to tran-scriptional changes in the nucleus. One NF-kB target genethat may provide a potentially relevant link with learningand memory is the a catalytic subunit of protein kinase A(PKA) [69]. PKA and one of its substrates, CREB, play keyroles in the formation of long-lasting memories [78]. Al-though PKA expression is reduced and forskolin-inducedCREB phosphorylation is impaired in the hippocampus ofCamKII-tTAtetOtn IkBa mice [69], alternative signalingpathways link synaptic activity and various extracellularsignals to CREBactivation [78]. Therefore, althoughNF-kBandCREBparticipate in a transcriptional network involvedin aspects of learning and memory, they do not necessarilyact in a mutually dependent sequential manner.

Alternative ways in which NF-kB signaling could affectlearning and memory relate to its roles in regulating thegrowth and morphology of axons and dendrites, as dis-cussed above. In particular, the possible influence of NF-kBsignaling on dendritic spine number andmorphology in theadult NAc in vivo [58,59] is pertinent given the relationshipbetween LTP/LTD induction and structural plasticity ofdendritic spines [79]. For these reasons, it will be impor-tant to examine whether NF-kB signaling is capable ofinfluencing spine turnover and morphology in other neu-rons in the developing and mature brain, and to ascertainin appropriate mouse genetic and other models if NF-kBsignaling in the hippocampus contributes to structuralplasticity of dendritic spines associated with learningand memory. Moreover, the recognition that NF-kB affectsthe elaboration of axons and dendrites during developmenthas potential implications for the interpretation of studiesof learning and memory in certain mouse genetic modelsthat lack key components of the NF-kB signaling systemfrom conception. The potential consequences of defectiveNF-kBduring developmentmay influence the performanceon a particular learning and memory task in the adult inways that are unrelated to the normal functions of NF-kBsignaling during training and recall in wild type mice.

An additional way in which NF-kB signaling mightinfluence learning and memory relates to its role in neu-rogenesis (Table 1). Several recent studies have implicatedNF-kB signaling in regulating neurogenesis during devel-opment and in the adult. NF-kB mediates the neurogeniceffect of erythropoietin in neurosphere cultures of neuralstem cells (NSCs) established from E14 mouse ganglioniceminence [80]. Additionally, cell proliferation is impairedin neurosphere cultures established from E13 mouse em-bryos that lack p65 and p50, compared with culturesestablished from wild type mice [11].

In the adult CNS, neurogenesis occurs in the subven-tricular zone (SVZ) of the lateral wall of the lateral ven-tricle and in the subgranular zone (SGZ) of the dentategyrus. In adult rats, stress activates interleukin-1b (IL-1b)/IL-1RI signaling, followed by the activation of NF-kBin NSCs in the SGV [14]. Inhibiting either IL-1b/IL-1RIsignaling or NF-kB activation prevents stress-inducedsuppression of hippocampal NSC proliferation, but doesnot affect NSC proliferation in non-stressed rats [14,81].Although NSC proliferation is likewise unaffected in theSGV of adult p50–/– mice, there is a marked deficiency inneurogenesis in the hippocampus of these mice as a resultof a defect in the late maturation of newly born neurons[13]. Inhibition of NF-kB in cultured adult neural progen-itor cells also significantly impairs their differentiationand inhibits the differentiation of these cells by toll-likereceptor 4 (TLR4) activation, a known activator of NF-kB[82]. NF-kB also mediates the in vitro proliferative re-sponse of adult SVZ NSCs to TNFa [12] and activation ofthe multi-ligand receptor RAGE (receptor for advancedglycation endproducts) [83], which may be relevant forenhancing NSC proliferation in brain inflammation andinjury [84].

Numerous studies demonstrating increased hippocam-pal neurogenesis following hippocampus-dependent, butnot hippocampus-independent, learning tasks togetherwith the detrimental effects of neurogenesis suppressionon performance of certain hippocampus-dependent learn-ing tasks, has established a potential link between neuro-genesis in the adult hippocampus and learning andmemory [85]. The deficiency in hippocampal neurogenesisand selective defect in short-term spatial memory perfor-mance in adult p50–/– mice [13] together with evidence forthe preferential recruitment of adult-generated granulecells into spatial memory networks in the dentate gyrus[86] is consistent with, but by no means proves, a contri-bution of NF-kB-regulated hippocampal neurogenesis toan aspect of hippocampal-dependent learning. Studies ofadult hippocampal neurogenesis in mice that have condi-tional mutations in various components of the NF-kBsignaling pathway combined with behavioral studies ofhippocampal-dependent learning tasks, may shed furtherlight on the potential link between NF-kB-regulated neu-rogenesis and learning and memory.

ConclusionsNF-kB signaling is becoming increasingly recognized as amajor regulator of the growth and morphology of neuralprocesses in the developing and mature nervous system.From the small number of peripheral and central neuronsthat have so far been investigated, NF-kB has been impli-cated in axonal and dendritic growth regulation from theearliest stages of process initiation to stages when neuronsare establishing functional connections during develop-ment to the regulation of dendrite spine number in adultneurons. These observations raise many outstanding ques-tions relating to the regulation and modulation of NF-kBsignaling and the identification of relevant NF-kB targetgenes that influence the development and structural plas-ticity of neural processes (Box 2). To date, most of the workon the influence of NF-kB signaling on the growth and

323

Box 2. Outstanding questions

� What is the physiological importance of the regulation of axonal

and dendritic growth by NF-kB signaling for neuronal develop-

ment in vivo, and is it relevant for only a subset of neurons or

does it exert a ubiquitous influence?

� To what extent does NF-kB signaling affect dendritic spine

structural plasticity in the adult nervous system and does it exert

any effects on presynaptic terminals?

� To what extent do NF-kB-dependent changes in axonal and

dendritic plasticity contribute to learning and memory?

� What are the in vivo physiological regulators of NF-kB signaling in

neurons that are relevant for controlling the growth, elaboration

and modification of neural processes?

� Which NF-kB-mediated changes in gene transcription are neces-

sary and sufficient for promoting or inhibiting the growth of

neural processes?

� Does NF-kB signaling affect the growth of axons and dendrites in

distinctive ways in the same neurons? Can NF-kB negatively

regulate dendritic growth in certain circumstances, as has been

demonstrated for axons?

� In addition to phosphorylation of p65 at S536, do other post-

translational modifications to NF-kB proteins influence the effects

of NF-kB signaling on the growth and morphology of neural

processes?

� In addition to transcriptional changes brought about by retro-

gradely transported activated NF-kB, does engagement of the NF-

kB signaling network exert any local effects on the cytoskeleton

that affect the morphology of axons and dendrites?


elaboration of neural processes has been carried out incultured primary neurons, and it will be important toclarify the physiological relevance of these observationsin vivo using viral vectors to manipulate NF-kB signalingand by using conditional gain-of-function or loss-of-func-tion approaches in transgenic mice. Such studies will likelyreveal important insights into the transcriptional net-works that regulate the establishment and refinement ofneuronal morphology and neural circuitry during develop-ment and structural plasticity in the mature nervoussystem.

AcknowledgmentsThe research of the authors is supported by the Wellcome Trust. Wethank Nuria Gavalda for assistance in the preparation of Box 1. Thebroad scope of this article and space constraints have not permittedcomprehensive citation of all of the relevant primary literature, for whichwe apologize.

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