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Surprisingly, no<jats:italic>Pax4<\/jats:italic>orthologous gene can be found in chicken and Xenopus<jats:italic>tropicalis<\/jats:italic>raising the question of the function of<jats:italic>pax4<\/jats:italic>gene in lower vertebrates such as in fish. In the present study, we have analyzed the expression and the function of the orthologous<jats:italic>pax4<\/jats:italic>gene in zebrafish.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>pax4<\/jats:italic>gene is transiently expressed in the pancreas of zebrafish embryos and is mostly restricted to endocrine precursors as well as to some differentiating \u03b4- and \u03b5-cells but was not detected in differentiating \u03b2-cells.<jats:italic>pax4<\/jats:italic>knock-down in zebrafish embryos caused a significant increase in \u03b1-cells number while having no apparent effect on \u03b2- and \u03b4-cell differentiation. This rise of \u03b1-cells is due to an up-regulation of the Arx transcription factor. Conversely, knock-down of<jats:italic>arx<\/jats:italic>caused to a complete loss of \u03b1-cells and a concomitant increase of<jats:italic>pax4<\/jats:italic>expression but had no effect on the number of \u03b2- and \u03b4-cells. In addition to the mutual repression between Arx and Pax4, these two transcription factors negatively regulate the transcription of their own gene. Interestingly, disruption of<jats:italic>pax4<\/jats:italic>RNA splicing or of<jats:italic>arx<\/jats:italic>RNA splicing by morpholinos targeting exon-intron junction sites caused a blockage of the altered transcripts in cell nuclei allowing an easy characterization of the<jats:italic>arx<\/jats:italic>- and<jats:italic>pax4<\/jats:italic>-deficient cells. Such analyses demonstrated that<jats:italic>arx<\/jats:italic>knock-down in zebrafish does not lead to a switch of cell fate, as reported in mouse, but rather blocks the cells in their differentiation process towards \u03b1-cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In zebrafish,<jats:italic>pax4<\/jats:italic>is not required for the generation of the first \u03b2- and \u03b4-cells deriving from the dorsal pancreatic bud, unlike its crucial role in the differentiation of these cell types in mouse. On the other hand, the mutual repression between Arx and Pax4 is observed in both mouse and zebrafish. These data suggests that the main original function of Pax4 during vertebrate evolution was to modulate the number of pancreatic \u03b1-cells and its role in \u03b2-cells differentiation appeared later in vertebrate evolution.<\/jats:p><\/jats:sec>","DOI":"10.1186\/1471-213x-12-37","type":"journal-article","created":{"date-parts":[[2012,12,17]],"date-time":"2012-12-17T23:14:13Z","timestamp":1355786053000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Pax4 is not essential for beta-cell differentiation in zebrafish embryos but modulates alpha-cell generation by repressing arx gene expression"],"prefix":"10.1186","volume":"12","author":[{"given":"Joachim","family":"Djiotsa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincianne","family":"Verbruggen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Giacomotto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minaka","family":"Ishibashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Manning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke","family":"Rinkwitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Manfroid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"L Voz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Peers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2012,12,17]]},"reference":[{"issue":"7","key":"714_CR1","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1038\/nrg841","volume":"3","author":"H Edlund","year":"2002","unstructured":"Edlund H: Pancreatic organogenesis\u2013developmental mechanisms and implications for therapy. 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