Unique aspects of transcriptional regulation in neurons - nuances in NFkappaB and Sp1-related factors

Abstract

The unique physiology and function of neurons create differences in their cellular physiology, including their regulation of gene expression. We began several years ago exploring the relationships between the NFκB transcription factor, neuronal survival, and glutamate receptor activation in telencephalic neurons. These studies led us to conclude that this population of cells is nearly incapable of activating the NFκB that is nonetheless expressed at reasonable levels. A subset of the κB cis elements are instead bound by members of the Sp1 family in neurons. Also surprising was our discovery that Sp1 itself, typically described as ubiquitous, is severely restricted in expression within forebrain neurons; Sp4 seems to be substituted during neuronal differentiation. These findings and their implications for neuronal differentiation -as well as potential dedifferentiation during degenerative processes -are discussed here. NFκB induction pathwaysNFκB consists of two subunits of Rel-family proteins, which include RelA (p65), RelB, cRel, p50, and p52 in mammalian cells [1]. RelA, RelB, and cRel subunits contain a transactivation domain; p50 and p52 do not. These subunits can form about a dozen different homo-and heterodimers. The best-characterized dimer is RelA/p50, also known as the canonical NFκB. Rel family proteins have a nuclear localization sequence (NLS) that permits their translocation to the nucleus upon activation, where they bind specific DNA sequences. The consensus bound by canonical NFκB is typically represented by GGGRN-NYYCC; other dimers have slightly different preferences [2]. NFκB activation is transient in most scenarios and terminated through the interaction between NFκB and the inhibitory κB proteins (IκBs) and also through degradation by proteasomal activity in the nucleus [3]. IκBs can mask the NLS of Rel proteins, and one of them (IκBα) has a nuclear export sequence (NES) through which the NFκB/IκBα complex is efficiently shuttled back to cytosol, restoring the inactive state. NFκB activation typically results from the breakdown of IκB proteins, an event requiring multiple steps. Once a stimulus activates the pathway, IκB kinases IKK1, IKK2, and IKK3 (the last is a scaffolding protein) are activated, phosphorylating IκBs [4]. Phosphorylated IκBs are degraded through the ubiquitin/proteasome pathway. The degradation of IκBs liberates NFκB and completes the activation cycle.

NFκB-Activated Astroglial Release of Complement C3 Compromises Neuronal Morphology and Function Associated with Alzheimer’s Disease

“…We and others have previously shown that astrocytes display prominent NFκB activity (Herkenham et al, 2011; Lian et al, 2012; Mao et al, 2009). Consistent with an astrocytic bias in NFκB signaling, we found that IκBα, a known downstream target of NFκB, was expressed at substantially higher levels in astroglia than in neurons under both basal (~5-fold) and TNFα-stimulated conditions (~50-fold) (Figure S1B).…”

“…These activities have been attributed, at least in part, to the presence of constitutive NFκB activity in neurons (Blondeau et al, 2001; Kaltschmidt et al, 2000; Kaltschmidt et al, 1993, 1995; Kaltschmidt et al, 1994). However, recent studies by us and others reported that, compared to astroglia, neurons exhibit negligible NFκB activity (Lian et al, 2012; Mao et al, 2009). Consistent with this assessment, we found that both IκBα and C3 are expressed at substantially higher levels in astroglia compared to neurons under both basal and TNFα-stimulated conditions.…”

Lipopolysacharide Rapidly and Completely Suppresses AgRP Neuron-Mediated Food Intake in Male Mice

“…Jang et al (35) further reported that the deletion of nuclear factor B (NF-B) signaling in POMC neurons prevented LPS-induced anorexia. However, it must be emphasized that the results of the latter study have been directly contradicted by a large body of literature demonstrating that NF-B signaling is largely unresponsive in neurons (67)(68)(69)(70). Additionally, the administration of peripheral LPS exclusively stimulated NF-B signaling in nonneuronal brain cells (71,72).…”

Genetic Variation in the KIAA0319 5′ Region as a Possible Contributor to Dyslexia

“…The insertion allele of rs71815143 is predicted to contain three Sp1 binding sites and a CCAAT/enhancer binding protein (C/EBP) binding site, which are not predicted for the deletion allele. Sp1 is a ubiquitous transcriptional activator, except in the CNS, where it is expressed exclusively in early forebrain neurons (Mao et al 2009). C/EBP recruits transcriptional activators to enhancer and promoter regions (Calella et al 2007).…”