The Transcription Factor NF-κB in Stem Cells and Development.

Christian Kaltschmidt,Barbara Kaltschmidt,Johannes F W Greiner

doi:10.3390/cells10082042

Abstract

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.

Highlights

Introduction to Canonical and NonCanonical NF-kB Signaling NF-κB was discovered in the laboratory of the Nobel Prize laureate David Baltimore as a latent transcription factor with inducible binding activity [1]
A KO of murine RELA resulted in embryonal lethality at E15-16 by the TNFα-mediated apoptosis of hepatocytes, while heterozygous RELA deletion is known to be associated with oral ulcers in patients
Conclude that, despite its broad evolutionary conservation, the role of NF-κB and its homologs during development extends from solely mediating dorsal–ventral patterning toward complex immune cell functionality and stem cell behavior

Summary

NF-κB in Development

We shed light on the universal concepts of NF-κB signaling (or that of its homologs) conserved during evolution by utilizing the evo-devo concept (evolutionary developmental biology, as reviewed in [22]). Drosophila has two NF-κB family members with DNA-binding domains: transactivating Dorsal (Dl) and DIF (or Dorsal-related immunity factor), with a typical REL homology domain, which is 45% identical to that of the mammalian counterparts c-REL, RELA, and RELB This high homology is surprisingly conserved for these proteins despite an evolutionary distance of more than 800 million years. The dorsoventral axis in Drosophila results in the formation of a gradient of the NF-κB RELA homolog Dl. Two to four hours after fertilization, the Dl gradient regulates various target genes. While the deletion of RELA in HEK 293 cells [45] or monoallelic inactivation in human fibroblasts [55] has no effect on TNF-α-mediated apoptosis, the oral mucosa of afflicted patients developed ulcers. We conclude that defects of REL in human cells profoundly affected the cell cycle, which might explain why no vital human mutant with c-REL defects has been observed to date (own literature search in 2021)

NF-κB Signaling in Embryonal Stem Cells

Findings

Discussion and Concluding