Abstract
Transcription factors in the CNC-bZIP family (NFE2, NRF1, NRF2 and NRF3) regulate genes with a wide range of functions in response to both physiological and exogenous signals, including those indicating changes in cellular redox status. Given their role in helping to maintain cellular homeostasis, it is imperative to understand the expression, regulation, and function of CNC-bZIP genes during embryonic development. We explored the expression and function of six nrf genes (nfe2, nrf1a, nrf1b, nrf2a, nrf2b, and nrf3) using zebrafish embryos as a model system. Analysis by microarray and quantitative RT-PCR showed that genes in the nrf family were expressed throughout development from oocytes to larvae. The spatial expression of nrf3 suggested a role in regulating the development of the brain, brachia and pectoral fins. Knock-down by morpholino anti-sense oligonucleotides suggested that none of the genes were necessary for embryonic viability, but nfe2 was required for proper cellular organization in the pneumatic duct and subsequent swim bladder function, as well as for proper formation of the otic vesicles. nrf genes were induced by the oxidant tert-butylhydroperoxide, and some of this response was regulated through family members Nrf2a and Nrf2b. Our results provide a foundation for understanding the role of nrf genes in normal development and in regulating the response to oxidative stress in vertebrate embryos.
Highlights
The nuclear factor-erythroid-2 (NFE2)-related factor (NRF) genes encode transcription factors in the Cap’n’Collar basic leucine zipper (CNC-bZIP) gene family
Nfe2-null mice lack circulating platelets [19], the Nrf1 knockout is embryonic lethal [20], Nrf2-null mice are highly sensitive to carcinogens and oxidative stress [21], and the Nrf3 knockout does not show abnormalities under normal conditions but is susceptible to lymphoma induced by exposure to carcinogens [22]
Because the data were normalized within each gene, expression values can be compared at different times for each gene but not across genes. nfe2 transcripts were maternally deposited, but levels fell substantially at 6 hpf and did not increase again until 48 hpf
Summary
The nuclear factor-erythroid-2 (NFE2)-related factor (NRF) genes encode transcription factors in the Cap’n’Collar basic leucine zipper (CNC-bZIP) gene family. NFE2 forms a heterodimeric transcription factor with small MAF proteins, regulates expression of globin genes [2,36], and may regulate the oxidative stress response in mature erythrocytes [17]. NRF1 in mammals is expressed in many tissues [4]; it plays a role in regulating redox balance in the liver [37] and in regulating genes involved in development [20], oxidative stress [38,39], cytoskeletal organization [40], and the proteasome [41]. NRF2 has a broad tissue distribution in mammals and acts as a pleiotropic transcription factor involved in regulating the susceptibility to disease, in mediating the response to xenobiotic exposure and oxidant stress, and in proteome maintenance [42]. We identify a novel role for nfe in the cellular organization of epithelia in the pneumatic duct
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