Landmark discovery of eye defects caused by Pax6 gene mutations in humans, rodents, and even fruit flies combined with Pax6 gene expression studies in various phyla, led to the master control gene hypothesis postulating that the gene is required almost universally for animal visual system development. However, this assumption has not been broadly tested in genetically trackable organisms such as vertebrates. Here, to determine the functional role of the fish orthologue of mammalian Pax6 in eye development we analyzed mutants in medaka Pax6.1 gene generated by genome editing. We found that transcription factors implicated in vertebrate lens development (Prox1a, MafB, c-Maf, FoxE3) failed to initiate expression in the presumptive lens tissue of Pax6.1 mutant fish resulting in aphakia, a phenotype observed previously in Pax6 mutant mice. Surprisingly, the overall differentiation potential of Pax6.1-deficient retinal progenitor cells (RPCs) is not severely compromised, and the only cell types affected by the absence of Pax6.1 transcription factor are retinal ganglion cells. This is in stark contrast to the situation in mice where the Pax6 gene is required cell-autonomously for the expansion of RPCs, and the differentiation of all retina cell types. Our results provide novel insight into the conserved and divergent roles of Pax6 gene orthologues in vertebrate eye development indicating that the lens-specific role is more evolutionarily conserved than the role in retina differentiation.

• Klíčová slova
• Pax6, eye evolution, gene expression, lens, retina, vision,
• Publikační typ
• časopisecké články MeSH

Chromatin remodeling complexes are required for many distinct nuclear processes such as transcription, DNA replication, and DNA repair. However, the contribution of these complexes to the development of complex tissues within an organism is poorly characterized. Imitation switch (ISWI) proteins are among the most evolutionarily conserved ATP-dependent chromatin remodeling factors and are represented by yeast Isw1/Isw2, and their vertebrate counterparts Snf2h (Smarca5) and Snf2l (Smarca1). In this study, we focused on the role of the Snf2h gene during the development of the mammalian retina. We show that Snf2h is expressed in both retinal progenitors and post-mitotic retinal cells. Using Snf2h conditional knockout mice (Snf2h cKO), we found that when Snf2h is deleted, the laminar structure of the adult retina is not retained, the overall thickness of the retina is significantly reduced compared with controls, and the outer nuclear layer (ONL) is completely missing. The depletion of Snf2h did not influence the ability of retinal progenitors to generate all the differentiated retinal cell types. Instead, the Snf2h function is critical for the proliferation of retinal progenitor cells. Cells lacking Snf2h have a defective S-phase, leading to the entire cell division process impairments. Although all retinal cell types appear to be specified in the absence of the Snf2h function, cell-cycle defects and concomitantly increased apoptosis in Snf2h cKO result in abnormal retina lamination, complete destruction of the photoreceptor layer, and consequently, a physiologically non-functional retina.

• Klíčová slova
• Smarca5, Snf2h, apoptosis, cell cycle, photoreceptors, retina,
• MeSH
• adenosintrifosfatasy * metabolismus   MeSH
• buněčné jádro metabolismus   MeSH
• chromatin * metabolismus   MeSH
• chromozomální proteiny, nehistonové * metabolismus   MeSH
• myši knockoutované MeSH
• myši MeSH
• proliferace buněk MeSH
• restrukturace chromatinu * MeSH
• retina MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• adenosintrifosfatasy * MeSH
• chromatin * MeSH
• chromozomální proteiny, nehistonové * MeSH
• Smarca5 protein, mouse MeSH Prohlížeč

During evolution, gene duplications lead to a naturally increased gene dosage. Duplicated genes can be further retained or eliminated over time by purifying selection pressure. The retention probability is increased by functional diversification and by the acquisition of novel functions. Interestingly, functionally diverged paralogous genes can maintain a certain level of functional redundancy and at least a partial ability to replace each other. In such cases, diversification probably occurred at the level of transcriptional regulation. Nevertheless, some duplicated genes can maintain functional redundancy after duplication and the ability to functionally compensate for the loss of each other. Many of them are involved in proper embryonic development. The development of particular tissues/organs and developmental processes can be more or less sensitive to the overall gene dosage. Alterations in the gene dosage or a decrease below a threshold level may have dramatic phenotypic consequences or even lead to embryonic lethality. The number of functional alleles of particular paralogous genes and their mutual cooperation and interactions influence the gene dosage, and therefore, these factors play a crucial role in development. This review will discuss individual interactions between paralogous genes and gene dosage sensitivity during development. The eye was used as a model system, but other tissues are also included.

• Klíčová slova
• duplication, embryonic development, eye, gene dosage, paralogous genes,
• MeSH
• duplikace genu * MeSH
• genová dávka MeSH
• molekulární evoluce * MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH