Regulation of neural process growth, elaboration and structural plasticity by NF-κB

Abstract

The nuclear factor-kappa B (NF-κB) family of transcription factors has recently emerged as a major regulator of the growth and elaboration of neural processes. NF-κB signaling has been implicated in controlling axon initiation, elongation, guidance and branching and in regulating dendrite arbor size and complexity during development and dendritic spine density in the adult. NF-κB is activated by a variety of extracellular signals, and either promotes or inhibits growth depending on the phosphorylation status of the p65 NF-κB subunit. These novel roles for NF-κB, together with recent evidence implicating NF-κB in the regulation of neurogenesis in the embryo and adult, have important implications for neural development and for learning and memory in the mature nervous system.

Figure 1

NF-κB signaling pathways regulating neurite growth from cultured neurons. In the canonical pathway (a,b), activated IKKβ phosphorylates (P) IκBα at Ser32 and Ser36, leading to its ubiquitination and degradation by the proteasome, allowing the released p65/p50 dimer to translocate to the nucleus. IKKβ can also phosphorylate p65 at the Ser 536 residue, which switches NF-κB to a neurite growth-inhibitory function. Of the many extracellular signals that activate the canonical pathway, TNFα binding to tumor necrosis factor receptor-1 (TNFR1) is among the most extensively studied and is known to operate in sympathetic neurons with resultant p65 phosphorylation and axonal growth inhibition (a) . 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 IKKβ 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) , although the upstream activators of this pathway have yet to be identified. In the TK-dependent pathway (c,d), IκBα 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 IκBα by Src and Lrk , whereas CNTF signaling during perinatal development activates the tyrosine kinase SYK, which in turn phosphorylates IκBα, leading to its removal without proteasome-dependent degradation . In hippocampal neurons (d), binding of NGF to the p75^NTR receptor results in PTPB1-dependent phosphorylation of IκBα by the tyrosine kinase Src .

Figure 2

Effects of selectively inhibiting NF-κB 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 IκBα. In the slice cultures, S32A/S36A IκBα-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-κB 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–IκBα-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 (panels a and b) and (panel c).

Figure I

Schematic diagram illustrating the mammalian members of the NF-κB and IκB families.