Abstract
NFκB signaling has a pivotal role in regulation of development, innate immunity, and inflammation. Ikk2 is one of the two critical kinases that regulate the NFκB signaling pathway. While the role of Ikk2 in immunity, inflammation and oncogenesis has received attention, an understanding of the role of Ikk2 in vertebrate development has been compounded by the embryonic lethality seen in mice lacking Ikk2. We find that despite abnormal angiogenesis in IKK2 zygotic mutants of zebrafish, the maternal activity of Ikk2 supports embryogenesis and maturation of fertile animals and allows to study the role of IKK2 in development. Maternal-zygotic ikk2 mutants represent the first vertebrates globally devoid of maternal and zygotic Ikk2 activity. They are defective in cell proliferation as evidenced by abnormal cytokinesis, nuclear enlargement and syncytialisation of a significant portion of blastoderm. We further document that reduced phosphorylation of Aurora A by Ikk2 could underlie the basis of these defects in cell division.
Highlights
A number of cellular and extracellular signals trigger the activation of the NFκB transcription factors[1, 2]
At midblastula transition (MBT) cells of early zebrafish embryo segregate into three different lineages – deep cells, which form the embryo proper, and two extraembryonic lineages – yolk syncytial layer (YSL) and enveloping layer (EVL)[32]
The genomic locus of ikk[2] contains 22 exons spanning 87.61 kb. It encodes a polypeptide of 779 aa residues that contains evolutionarily conserved kinase, ubiquitine-like (ULD), leucine zipper (LZ), helix-loop-helix (HLH) and NEMO-binding (NBD) domains (Figs 1A; S1A)
Summary
To study the role of Ikk[2] in development, we cloned it from total RNA of 96 hpf zebrafish. It seems that the ntl-like phenotype develops due to incomplete inhibition of Ikk2-NFκB activity In both embryos and adult mutants neither hepatic apoptosis nor liver failure were observed in ikk2−/− zebrafish. Recent advance in human genetics leads to the identification human patients with IKK2 mutations[18,19,20] and studies based on their phenotype seems to reinforce its role in immunity as patients all develop Severe Combined Immunodeficiency (SCID) within the first 6 month of age, which is attributed to the loss of function of canonical NFκB signalling. As zebrafish ikk1−/− mutants survive to adulthood without obvious morphological problem, whereas MZikk1−/− cannot differentiate into a proper embryonic ectoderm[44], it is obvious that Ikk[1] and Ikk[2] have their own individual roles in epidermal development, which possibly explains the skin phenotype observed at later stages in zygotic mutants as well as other in other model systems. The establishment of zebrafish ikk[2] mutants and their functional analysis offer an attractive alternative approach in understanding the physiological function of IKK2 that complements current knowledge based on mammalian models and changes our perspective on a developmental role of the NFκB signalling pathway in vertebrates
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