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  current news   Press   selected story    
     
  25th January 2013  
  Sequencing of Pax6 loci from the elephant shark reveals a family of Pax6 genes in vertebrate genomes, forged by ancient duplications and divergences
 
 




Authors
Vydianathan Ravi1,¶, Shipra Bhatia2,¶, Phillippe Gautier2, Felix Loosli3, Boon-Hui Tay1, Alice Tay1, Emma Murdoch2, Pedro Coutinho2, Veronica van Heyningen2, Sydney Brenner1, Byrappa Venkatesh1,* and Dirk A. Kleinjan2,*

1 -
Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Biopolis, Singapore 138673, Singapore.
2 -
MRC Human Genetics Unit at the MRC IGMM at the University of Edinburgh, EdinburghEH4 2XU, United Kingdom.
3 -

Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Hermann von Helmholtz Platz 1, D-76344 Eggenstein-Leopoldshafen, Germany.

¶ - joint first-authors
* - Corresponding authors

Published in PLoS Genetics on 24 January 2013.
To read paper, please click here.

Abstract

Pax6 is a developmental control gene essential for eye development throughout the animal kingdom. In addition, Pax6 plays key roles in other parts of the CNS, olfactory system and pancreas. In mammals a single Pax6 gene encoding multiple isoforms delivers these pleiotropic functions. Here we provide evidence that the genomes of many other vertebrate species contain multiple Pax6 loci. We sequenced Pax6-containing BACs from the cartilaginous elephant shark (Callorhinchus milii), and found two distinct Pax6 loci in its genome. Pax6.1 is highly similar to mammalian Pax6, while Pax6.2 encodes a paired-less Pax6. Using synteny relationships we identify homologs of this novel paired-less Pax6.2 gene in lizard, frog, as well as in zebrafish and other teleosts. In zebrafish two full-length Pax6 duplicates were known previously, originating from the fish-specific genome duplication (FSGD) and expressed in divergent patterns due to paralog-specific loss of cis-elements. We show that teleosts other than zebrafish also maintain duplicate full-length Pax6 loci, but differences in gene and regulatory domain structure suggest that these Pax6 paralogs originate from a more ancient duplication event, and are hence renamed as Pax6.3. Sequence comparisons between mammalian and elephant shark Pax6.1 loci highlight the presence of short- and long-range conserved noncoding elements (CNEs). Functional analysis demonstrates the ancient role of long-range enhancers for Pax6 transcription. We show that the paired-less Pax6.2 ortholog in zebrafish is expressed specifically in the developing retina. Transgenic analysis of elephant shark and zebrafish Pax6.2 CNEs with homology to the mouse NRE/Pα internal promoter revealed highly specific retinal expression. Finally, morpholino depletion of zebrafish Pax6.2 resulted in a 'small eye' phenotype, supporting a role in retinal development. In summary, our study reveals that the pleiotropic functions of Pax6 in vertebrates are served by a divergent family of Pax6 genes, forged by ancient duplication events and independent, lineage-specific gene losses.

Figure Legend:
Functional assay of PAX6 conserved noncoding element (CNE) -200 in transgenic zebrafish and mouse. Upper panel: VISTA plot of PAX6 locus from human, mouse, chicken, zebrafish (Pax6a and b copies) and elephant shark. The human sequence (x-axis) was used as base and a cut-off of ≥70% identity and >100 bp window size was used for identifying CNEs. The y-axis represents percent identity and shaded peaks represent CNEs (pink) and conserved exons (blue). CNE-200 is present in human, mouse, chicken, zebrafish-a, and elephant shark PAX6 loci but lost in zebrafish-b. Middle panel: Transgenic assay of human CNE-200 in zebrafish (A-C). Lateral view of an E-200-gata2-GFP reporter line showing expression in olfactory bulbs (OB) and hindbrain (HB) in a 48 hpf of zebrafish embryo (A); ventral (B) and dorsal (C) views of the embryo head region showing expression in the OB and HB, respectively. Lower panel: Transgenic assay of human CNE-200 in mouse (H-J). LacZ reporter mouse transgenics using the human CNE-200 element (H-J). Expression in the neural tube is intrinsic to the Hsp68-LacZ cassette (H); expression starts to appear from E12.5 in the olfactory tracts at the base of the cortex (I); at E15.5 (J) expression is seen in OB, lateral olfactory tracts (LOT) and a thin band in the dorsal cerebellum (CB).


For more information on Byrappa VENKATESH's laboratory, please click here.