August 10, 2021;
The Transcription Factor NF-κB in Stem Cells and Development.
NF-κB (nuclear factor kappa B) belongs to a family of transcription factors known to regulate a broad range of processes such as immune cell function, proliferation and cancer, neuroprotection, and long-term memory. Upcoming fields of NF-κB research include its role in stem cells and developmental processes. In the present review, we discuss one role of NF-κB in development in Drosophila, Xenopus, mice, and humans in accordance with the concept of evo-devo (evolutionary developmental biology). REL domain-containing proteins of the NF-κB family are evolutionarily conserved among these species. In addition, we summarize cellular phenotypes such as defective B- and T-cell compartments related to genetic NF-κB defects detected among different species. While NF-κB proteins are present in nearly all differentiated cell types, mouse and human embryonic stem cells do not contain NF-κB proteins, potentially due to miRNA-dependent inhibition. However, the mesodermal and neuroectodermal differentiation of mouse and human embryonic stem cells is hampered upon the repression of NF-κB. We further discuss NF-κB as a crucial regulator of differentiation in adult stem cells such as neural crest-derived and mesenchymal stem cells. In particular, c-REL seems to be important for neuronal differentiation and the neuroprotection of human adult stem cells, while RELA plays a crucial role in osteogenic and mesodermal differentiation.
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Schematic view of canonical and non-canoncial NF-κB signaling in mammals. In canonical signaling, NF-κB exists in two forms: a latent form complexed with IκB retained within the cytoplasm, and activated NF-κB without inhibitory subunits, binding to DNA in the nucleus. Various extracellular stimuli activate NF-κB, such as bacterial and viral products, inflammatory cytokines, reactive oxygen species, ultraviolet light, and even neurotransmitters. Intracellularly, a kinase complex (IKK, IκB kinase) is activated, in turn, resulting in phosphorylation and linear ubiquitination of the heterodimer-associated IκB. Rapid degradation of IκB through ubiquitin-mediated proteasomal degradation is followed by nuclear import of NF-κB and binding to target gene promoters such as IκB. Later, IκB can enter the nucleus and terminate the expression of NF-κB-target genes. In non-canonical signaling, binding of ligands to respective receptors such as BAFFR leads to NF-κB-inducing kinase (NIK)-mediated phosphorylation of IKK1, which in turn results in processing of p100 to p52 and enables the translocation of p52/RELB into the nucleus and the initiation of target gene transcription. Expression patterns in human single cells measured by RNA sequencing differed considerably. Whereas RELA has low cell type-specificity, c-REL is predominantly expressed in monocytes and keratinocytes and RELB in monocytes and glandular cells (The Human Protein Atlas, www.proteinatlas.org (accessed on 23 July 2021)).
Schematic view of the fly Drosophila melanogaster’s development (in (A–C)), also shown in comparison to that of vertebrates such as the frog Xenopus laevis and humans (in (D)). A fertilized Drosophila egg (A) starts to divide and forms an embryo where the cytoplasm is shared between all nuclei (syncytium, (B)). At this stage of development, a dorsoventral gradient initiates the nuclear localization of Dorsal (Dl, blue), which is the fly homolog of vertebrate NF-κB. Dl is nuclear in the ventral region, as can be seen in the cross-section of the fly embryo depicted in (C). Nuclei without Dl are depicted in red, and a graded amount of nuclear Dorsal is depicted in shades of blue, with the maximal Dl concentration in dark blue. Extracellular regulators such as Decapentaplegic (Dpp) inhibit nuclear orsal, whereas Dpp is inhibited by its antagonist Sog (short gastrulation protein). Vertebrates do not have a ventral nerve cord but have a spinal cord; thus, it would not be entirely surprising if molecular regulators were also turned in their orientation from ventral to dorsal. BMP-4, a homolog of Dpp, is expressed in the ventral domain (D), whereas Chordin, a homolog of Sog, is expressed in the dorsal domain.