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

The cell type-specific expression of key transcription factors is central to development and disease. Brachyury/T/TBXT is a major transcription factor for gastrulation, tailbud patterning, and notochord formation; however, how its expression is controlled in the mammalian notochord has remained elusive. Here, we identify the complement of notochord-specific enhancers in the mammalian Brachyury/T/TBXT gene. Using transgenic assays in zebrafish, axolotl, and mouse, we discover three conserved Brachyury-controlling notochord enhancers, T3, C, and I, in human, mouse, and marsupial genomes. Acting as Brachyury-responsive, auto-regulatory shadow enhancers, in cis deletion of all three enhancers in mouse abolishes Brachyury/T/Tbxt expression selectively in the notochord, causing specific trunk and neural tube defects without gastrulation or tailbud defects. The three Brachyury-driving notochord enhancers are conserved beyond mammals in the brachyury/tbxtb loci of fishes, dating their origin to the last common ancestor of jawed vertebrates. Our data define the vertebrate enhancers for Brachyury/T/TBXTB notochord expression through an auto-regulatory mechanism that conveys robustness and adaptability as ancient basis for axis development.

• MeSH
• chorda dorsalis * metabolismus   MeSH
• dánio pruhované * genetika   metabolismus   MeSH
• fetální proteiny genetika   metabolismus   MeSH
• lidé MeSH
• myši MeSH
• protein brachyurie MeSH
• proteiny T-boxu genetika   metabolismus   MeSH
• savci genetika   MeSH
• vývojová regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• fetální proteiny MeSH
• protein brachyurie MeSH
• proteiny T-boxu MeSH
• TBX1 protein, human MeSH Prohlížeč
• Tbx1 protein, mouse MeSH Prohlížeč

The cell type-specific expression of key transcription factors is central to development. Brachyury/T/TBXT is a major transcription factor for gastrulation, tailbud patterning, and notochord formation; however, how its expression is controlled in the mammalian notochord has remained elusive. Here, we identify the complement of notochord-specific enhancers in the mammalian Brachyury/T/TBXT gene. Using transgenic assays in zebrafish, axolotl, and mouse, we discover three Brachyury-controlling notochord enhancers T3, C, and I in human, mouse, and marsupial genomes. Acting as Brachyury-responsive, auto-regulatory shadow enhancers, deletion of all three enhancers in mouse abolishes Brachyury/T expression selectively in the notochord, causing specific trunk and neural tube defects without gastrulation or tailbud defects. Sequence and functional conservation of Brachyury-driving notochord enhancers with the brachyury/tbxtb loci from diverse lineages of fishes dates their origin to the last common ancestor of jawed vertebrates. Our data define the enhancers for Brachyury/T/TBXTB notochord expression as ancient mechanism in axis development.

• Publikační typ
• časopisecké články MeSH
• preprinty MeSH

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

The vertebrate eye is derived from the neuroepithelium, surface ectoderm, and extracellular mesenchyme. The neuroepithelium forms an optic cup in which the spatial separation of three domains is established, namely, the region of multipotent retinal progenitor cells (RPCs), the ciliary margin zone (CMZ)-which possesses both a neurogenic and nonneurogenic potential-and the optic disk (OD), the interface between the optic stalk and the neuroretina. Here, we show by genetic ablation in the developing optic cup that Meis1 and Meis2 homeobox genes function redundantly to maintain the retinal progenitor pool while they simultaneously suppress the expression of genes characteristic of CMZ and OD fates. Furthermore, we demonstrate that Meis transcription factors bind regulatory regions of RPC-, CMZ-, and OD-specific genes, thus providing a mechanistic insight into the Meis-dependent gene regulatory network. Our work uncovers the essential role of Meis1 and Meis2 as regulators of cell fate competence, which organize spatial territories in the vertebrate eye.

• Klíčová slova
• Meis, development, retina,
• MeSH
• buněčná diferenciace genetika   MeSH
• genový knockdown MeSH
• homeodoménové proteiny genetika   metabolismus   MeSH
• kmenové buňky cytologie   metabolismus   MeSH
• obratlovci MeSH
• retina cytologie   metabolismus   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• vývojová regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• homeodoménové proteiny MeSH
• transkripční faktory MeSH

Cranial neural crest cells (cNCCs) originate in the anterior neural tube and populate pharyngeal arches in which they contribute to formation of bone and cartilage. This cell population also provides molecular signals for the development of tissues of non-neural crest origin, such as the tongue muscles, teeth enamel or gland epithelium. Here we show that the transcription factor Meis2 is expressed in the oral region of the first pharyngeal arch (PA1) and later in the tongue primordium. Conditional inactivation of Meis2 in cNCCs resulted in loss of Sonic hedgehog signalling in the oropharyngeal epithelium and impaired patterning of PA1 along the lateral-medial and oral-aboral axis. Failure of molecular specification of PA1, illustrated by altered expression of Hand1/2, Dlx5, Barx1, Gsc and other markers, led to hypoplastic tongue and ectopic ossification of the mandible. Meis2-mutant mice thus display craniofacial defects that are reminiscent of several human syndromes and patients with mutations in the Meis2 gene.

• Klíčová slova
• Craniofacial, Meis, Pharyngeal arch, Sonic hedgehog (Shh) signalling,
• MeSH
• alely MeSH
• biologické markery MeSH
• crista neuralis cytologie   embryologie   MeSH
• delece genu MeSH
• fenotyp MeSH
• homeodoménové proteiny genetika   metabolismus   MeSH
• imunohistochemie MeSH
• kalcinóza genetika   metabolismus   MeSH
• mandibula embryologie   MeSH
• myši transgenní MeSH
• myši MeSH
• organogeneze genetika   MeSH
• proteiny hedgehog metabolismus   MeSH
• rozvržení tělního plánu * genetika   MeSH
• signální transdukce * MeSH
• zubní oblouk embryologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery MeSH
• homeodoménové proteiny MeSH
• Mrg1 protein, mouse MeSH Prohlížeč
• proteiny hedgehog MeSH