The NF-κB family: Key players during embryonic development and HSC emergence  Raquel Espín-Palazón, David Traver  Experimental Hematology  Volume 44, Issue 7, Pages 519-527 (July 2016) DOI: 10.1016/j.exphem.2016.03.010 Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions

Experimental Hematology 2016 44, 519-527DOI: (10. 1016/j. exphem. 2016 Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions

Figure 1 Canonical versus noncanonical activation of NF-κB pathway and its role during development. Briefly, in the canonical NF-κB pathway (A), the activation of canonical NF-κB receptors TNFRs, IL-1R, TLRs, as well as TCR and BCR (not represented here), by their respective ligands converge into IKKβ activation. Activated IKKβ phosphorylates IκBα on serine residues S32 and S36, which will lead to its separation from the p65/p50 complex and degradation. Free p65/p50 heterodimers can then translocate to the nucleus and regulate target gene transcription. In the noncanonical NF-κB signaling pathway (B), activation of noncanonical NF-κB receptors, such as (LT)βR, BAFFR, RANK, or CD40, triggers IKKα phosphorylation and activation by NIK. Activated IKKα then phosphorylates p100 on serine residues S866 and S870, leading to p100 polyubiquitination and partial processing to p52. p52/RelB heterotrimers transcolate to the nucleus to regulate specific gene expression. BAFFR=B-cell activation factor; BCR=B-cell receptor; CD40 = cluster of differentiation 40; (LT)βR = lymphotoxin β–receptor; RANK = receptor activator for NF-κB; TCR = T-cell receptor; TLR = toll-like receptor; TNFR = tumor necrosis factor receptor. Experimental Hematology 2016 44, 519-527DOI: (10.1016/j.exphem.2016.03.010) Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions

Figure 2 Developmental defects observed during embryogenesis that are associated with manipulation of NF-κB pathway elements. Illustration depicts a vertebrate embryo showing the organs/tissues that are developmentally altered after NF-κB pathway disruption. Experimental Hematology 2016 44, 519-527DOI: (10.1016/j.exphem.2016.03.010) Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions

Figure 3 NF-κB is required for HSC specification. Tnfa produced by neutrophils binds Tnfr2 in the hemogenic endothelium to activate NF-κB. NF-κB can also be activated by Gcsfr and Tlr4, the latter through Myd88. Activation of Tnfr2 leads to jag1a gene expression, possibly mediated by NF-κB. NF-κB and jag1a activate Notch, which leads to HSC specification. Ifnγ, another pro-inflammatory cytokine involved in HSC specification, is downstream of Notch signaling during this process. Experimental Hematology 2016 44, 519-527DOI: (10.1016/j.exphem.2016.03.010) Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions