Duplicate <it>dmbx1 </it>genes regulate progenitor cell cycle and differentiation during zebrafish midbrain and retinal development

• Main Authors: Chang Belinda SW, Kuo Claire, Weadick Cameron J, Wong Loksum, Tropepe Vincent
• Format: Article
• Language: English
• Published: BMC 2010-09-01
• Series: BMC Developmental Biology
• Online Access: http://www.biomedcentral.com/1471-213X/10/100

<p>Abstract</p> <p>Background</p> <p>The <it>Dmbx1 </it>gene is important for the development of the midbrain and hindbrain, and mouse gene targeting experiments reveal that this gene is required for mediating postnatal and adult feeding behaviours. A single <it>Dmbx1 </it>gene exists in terrestrial vertebrate genomes, while teleost genomes have at least two paralogs. We compared the loss of function of the zebrafish <it>dmbx1a </it>and <it>dmbx1b </it>genes in order to gain insight into the molecular mechanism by which <it>dmbx1 </it>regulates neurogenesis, and to begin to understand why these duplicate genes have been retained in the zebrafish genome.</p> <p>Results</p> <p>Using gene knockdown experiments we examined the function of the <it>dmbx1 </it>gene paralogs in zebrafish, <it>dmbx1a </it>and <it>dmbx1b </it>in regulating neurogenesis in the developing retina and midbrain. Dose-dependent loss of <it>dmbx1a </it>and <it>dmbx1b </it>function causes a significant reduction in growth of the midbrain and retina that is evident between 48-72 hpf. We show that this phenotype is not due to patterning defects or persistent cell death, but rather a deficit in progenitor cell cycle exit and differentiation. Analyses of the morphant retina or anterior hindbrain indicate that paralogous function is partially diverged since loss of <it>dmbx1a </it>is more severe than loss of <it>dmbx1b</it>. Molecular evolutionary analyses of the <it>Dmbx1 </it>genes suggest that while this gene family is conservative in its evolution, there was a dramatic change in selective constraint after the duplication event that gave rise to the <it>dmbx1a </it>and <it>dmbx1b </it>gene families in teleost fish, suggestive of positive selection. Interestingly, in contrast to zebrafish <it>dmbx1a</it>, over expression of the mouse <it>Dmbx1 </it>gene does not functionally compensate for the zebrafish <it>dmbx1a </it>knockdown phenotype, while over expression of the <it>dmbx1b </it>gene only partially compensates for the <it>dmbx1a </it>knockdown phenotype.</p> <p>Conclusion</p> <p>Our data suggest that both zebrafish <it>dmbx1a </it>and <it>dmbx1b </it>genes are retained in the fish genome due to their requirement during midbrain and retinal neurogenesis, although their function is partially diverged. At the cellular level, Dmbx1 regulates cell cycle exit and differentiation of progenitor cells. The unexpected observation of putative post-duplication positive selection of teleost Dmbx1 genes, especially <it>dmbx1a</it>, and the differences in functionality between the mouse and zebrafish genes suggests that the teleost <it>Dmbx1 </it>genes may have evolved a diverged function in the regulation of neurogenesis.</p>