**4. Regulation of neural induction and neural plate patterning by NFκB signaling**

NFκB signaling is essential for embryonic development (http://www.bu.edu/nf-kb/gene-re‐ sources/gene-knockouts/) because p65 knockout mice died on E15 and p65/p50 or p65/c-rel double knockout mice died on E13 due to liver degeneration [63, 64]. Such embryonic lethal‐ ity precluded further investigation on the role of NFκB in late embryonic brain develop‐ ment. Additional knockout of TNF receptor 1 (TNFR1) in these p65-null mice rescued embryonic lethality [65], providing an opportunity to investigate the role of NFκB signaling in regulating embryonic neurogenesis [34]. However, the distribution pattern of NSCs/NPCs and cell lineage analysis in neurogenic zones of these mutants have not yet been examined. IKKα/IKKβ double knockout mice died on E12 due to apoptosis of NECs leading to impair‐ ments in neurogenesis [66].

Several lines of clinical studies identified the correlation of NFκB signaling defects to vari‐ ous neurodevelopmental disorders. Among 6 genes associated with nonsyndromic autoso‐ mal-recessive mental retardation [67, 68, 69], two, NIK- and IKKβ-binding protein (NIBP) [67, 68, 69] and coiled-coil and C2 domain-containing protein 2A (CC2D1A) [70, 71], have been shown to regulate NFκB signaling through the classical IKKβ pathway, implying the important role of NFκB signaling in mental retardation and possibly other neurodevelop‐ mental diseases. In autism spectrum disorders, activation of NFκB signaling is significantly increased [72, 73, 74], although the role and mechanism of the activated NFκB signaling re‐ main to be determined.

During neural induction, the ectodermal epithelial cells transit into NECs due to the inhibi‐ tion of bone morphogenetic protein (BMP) signaling by the neural inducer (Chordin, Nog‐ gin and Follistatin). In this original "default model", high activity of BMP signaling defines epidermis, while absence of BMP specifies neural plate [75, 76, 77]. However, this model can no longer explain the complicate process of neural induction, which involves additional sig‐ naling pathways such as Wnt/β-catenin, FGF, Sox2, and Notch signaling [77, 78, 79, 80, 81, 82]. NFκB signaling is shown to inhibit BMP signaling in oesteoblastogenesis [83, 84]. We speculate that NFκB may regulate neural induction. Previous studies showed that the grad‐ ed activation of NFκB/c-rel protein in the dorsal region determine the dorsal-ventral pat‐ terning in Drosophila [85, 86, 87, 88] and Xenopus laevis [89]. During mouse embryogenesis, virtually all members of the NFκB pathway are expressed in embryonic, trophoblast, and uterine cells [90]. It is proposed that NFκB may protect the embryos exposed to embryopath‐ ic stresses, possibly through its anti-apoptotic effect [90]. However, there is no direct evi‐ dence for the role of NFκB signaling in the *in vivo* neural induction (Figure 5).

maintain pluripotency [100]. ES cell-specific miR-290 maintains the pluripotency and self-re‐ newal of ES cells through repressing classical NFκB signaling [107]. Forced expression of p65 causes loss of pluripotency, promotes differentiation of ES cells, and leads to an epithe‐ lial to mesenchymal transition [107]. These data define p65 as a novel target gene of miR-290 cluster and provide new insight into the function of ES cell-specific miRNAs [107]. Taken altogether, NFκB signaling is activated and required during the early differentiation of vari‐

**Stage-specific effects of NF**k**B signaling**

**Neural induction and neural fate decision**

**6. Promotion of iPS reprograming by pharmacological or genetic**

fast generation of iPS for drug discovery and cell transplantation studies.

**7. Concluding remark and future direction**

**Figure 5.** Potential regulatory sites of NFκB signaling during neuronal cell fate decision. Solid green arrows indicate the sites supported by limited reports, while the dotted red arrows indicate the stages that need experimental sup‐ ports. ESC, embryonic stem cells; EB, embryoid body; NEC, neural epithelial cells; NSCs, neural stem cells; NPCs, neural

Various somatic cells have been successfully reprogramed into the ES-like pluripotent stem cells by a combination of factors or a single factor [108, 109]. During the reprogramming process, the classical NFκB signaling is inhibited [103, 106, 107]. Therefore, we speculate that NFκB inhibition might directly induce or promote the reprograming of iPS. Many specific inhibitors for NFκB signaling have been developed and some of them are applied to clinical trial [110]. In addition, fibroblasts or other somatic cells from transgenic mice deficient in NFκB signaling or clinical patients with mutation of NFκB signaling components can be easily accessible. It will be imperative to use NFκB inhibitors or genetic sources for easy and

NFκB signaling is a key mediator for numerous niche factors that regulate various stages or phases of neural induction and neurogenesis. The classical pathway of NFκB activation plays important role in regulating selfrenewal/multipotency and early differentiation of

**EB NEC Rossette NSCs NPCs Neuroblast Neuron**

NFκB Signaling Directs Neuronal Fate Decision

http://dx.doi.org/10.5772/53503

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ous stem cells and embryogenesis (Figure 5).

**stage ESC**

**Zygotes 2-cell** 

**inhibition of NFκB signaling.**

progenitor cells.
