Otx genes in the evolution of the vertebrate brain.
Journal - Brain research bulletin (United States )
Only until a decade ago, animal phylogeny was traditionally based on the assumption that evolution of bilaterians went from simple to complex through gradual steps in which the extant species would represent grades of intermediate complexity that reflect the organizational levels of their ancestors. The advent of more sophisticated molecular biology techniques combined to an increasing variety of functional experiments has provided new tools, which lead us to consider evolutionary studies under a brand new light. An ancestral versus derived low-complexity of a given organism has now to be carefully re-assessed and also the molecular data so far accumulated needs to be re-evaluated. Conserved gene families expressed in the nervous system of all the species have been extensively used to reconstruct evolutionary steps, which may lead to identify the morphological as well as molecular features of the last common ancestor of bilaterians (Urbilateria). The Otx gene family is among these and will be here reviewed.
|ISSN : ||0361-9230|
|Mesh Heading : ||Animals Brain Genomics Phylogeny Vertebrates|
|Mesh Heading Relevant : ||Evolution metabolism|
OTX1 compensates for OTX2 requirement in regionalisation of anterior neuroectoderm.
Journal - Gene expression patterns : GEP (Netherlands )
Otx genes play a relevant role in specification, maintenance and patterning of anterior neuroectoderm. OTX1 and OTX2 proteins share extensive codogenic similarity even though in OTX1 these regions of homology are separated by stretches of amino acid insertions. From 1 to 3 somites stage onwards, Otx1 and Otx2 are largely coexpressed, but only Otx2 is expressed during gastrulation. To determine whether OTX1 and OTX2 gene products share common biochemical properties, mouse models replacing Otx1 with Otx2 and vice versa have been generated. These studies have indicated a remarkable functional equivalence between the two proteins. Nevertheless, it was still debated whether OTX1 is functionally equivalent to OTX2 in early anterior neuroectoderm. To address this issue we generated a new mouse model (hOtx1(2FL)) replacing only the coding sequence and introns of Otx2 with the human Otx1 codogenic sequence. hOtx1(2FL/2FL) and hOtx1(2FL/-) mice were viable, fertile and exhibited an apparently normal behaviour. hOtx1 mRNA was correctly transcribed under the Otx2 transcriptional control and, similarly, the hOTX1 protein was properly distributed and quantitatively very similar if not identical to that of OTX2. Patterning and regionalisation of forebrain and midbrain were unaffected as revealed by the expression of diagnostic genes which are highly sensitive to reduction of OTX proteins, such as Fgf8, Pax2 and Gbx2.
|ISSN : ||1567-133X|
|Mesh Heading : ||Animals Body Patterning DNA-Binding Proteins Ectoderm Female Fibroblast Growth Factor 8 Fibroblast Growth Factors Gene Expression Regulation, Developmental Homeodomain Proteins Humans In Situ Hybridization Male Mesencephalon Mice Mice, Inbred C57BL Mice, Knockout Nerve Tissue Proteins Otx Transcription Factors PAX2 Transcription Factor Phenotype Prosencephalon RNA, Messenger Trans-Activators Transcription Factors genetics metabolism genetics metabolism genetics metabolism genetics genetics genetics metabolism|
|Mesh Heading Relevant : ||physiology physiology embryology physiology embryology physiology physiology|
OTD/OTX2 functional equivalence depends on 5' and 3' UTR-mediated control of Otx2 mRNA for nucleo-cytoplasmic export and epiblast-restricted translation.
Journal - Development (Cambridge, England) (England )
How gene activity is translated into phenotype and how it can modify morphogenetic pathways is of central importance when studying the evolution of regulatory control mechanisms. Previous studies in mouse have suggested that, despite the homeodomain-restricted homology, Drosophila orthodenticle (otd) and murine Otx1 genes share functional equivalence and that translation of Otx2 mRNA in epiblast and neuroectoderm might require a cell type-specific post-transcriptional control depending on its 5' and 3' untranslated sequences (UTRs). In order to study whether OTD is functionally equivalent to OTX2 and whether synthesis of OTD in epiblast is molecularly dependent on the post-transcriptional control of Otx2 mRNA, we generated a first mouse model (otd(2)) in which an Otx2 region including 213 bp of the 5' UTR, exons, introns and the 3' UTR was replaced by an otd cDNA and a second mutant (otd(2FL)) replacing only exons and introns of Otx2 with the otd coding sequence fused to intact 5' and 3' UTRs of Otx2. otd(2) and otd(2FL) mRNAs were properly transcribed under the Otx2 transcriptional control, but mRNA translation in epiblast and neuroectoderm occurred only in otd(2FL) mutants. Phenotypic analysis revealed that visceral endoderm (VE)-restricted translation of otd(2) mRNA was sufficient to rescue Otx2 requirement for early anterior patterning and proper gastrulation but it failed to maintain forebrain and midbrain identity. Importantly, epiblast and neuroectoderm translation of otd(2FL) mRNA rescued maintenance of anterior patterning as it did in a third mouse model replacing, as in otd(2FL), exons and introns of Otx2 with an Otx2 cDNA (Otx2(2c)). The molecular analysis has revealed that Otx2 5' and 3' UTR sequences, deleted in the otd(2) mRNA, are required for nucleo-cytoplasmic export and epiblast-restricted translation. Indeed, these molecular impairments were completely rescued in otd(2FL) and Otx2(2c) mutants. These data provide novel in vivo evidence supporting the concept that during evolution pre-existing gene functions have been recruited into new developmental pathways by modifying their regulatory control.
|ISSN : ||0950-1991|
|Mesh Heading : ||3' Untranslated Regions 5' Untranslated Regions Active Transport, Cell Nucleus Animals Body Patterning Brain Cytoplasm DNA, Complementary Drosophila Drosophila Proteins Evolution Homeodomain Proteins Mice Mice, Knockout Morphogenesis Nerve Tissue Proteins Otx Transcription Factors Phenotype Protein Biosynthesis RNA, Messenger Species Specificity Trans-Activators genetics embryology metabolism metabolism genetics embryology genetics|
|Mesh Heading Relevant : ||genetics genetics genetics metabolism genetics|
Otx genes in evolution: are they involved in instructing the vertebrate brain morphology?
Journal - Journal of Anatomy
Previous mouse models have indicated that Otx1 and Otx2 play an important role in brain and sense organ development and, together with the Drosophila orthodenticle (otd) gene, they share a high degree of reciprocal functional equivalence. Interestingly, mouse models replacing the same region of the Otx2 locus with Otx1, otd or lacZ genes have revealed the existence of a differential post-transcriptional control between the visceral endoderm (VE) and epiblast cells. Indeed Otx1, otd or lacZ mRNA were transcribed in both tissues but translated only in the VE. Embryos lacking OTX1 or OTD proteins in the epiblast and derived tissues, such as the neuroectoderm and axial mesendoderm (AME), fail to maintain the anterior identity and result in a headless phenotype. This finding leads us to hypothesise that, during evolution, the specification of the vertebrate-type brain may have required epiblast cells to translate Otx2 mRNA in order to establish maintenance properties. The establishment of this regulatory control might have been reflected into a remarkable reorganisation of the rostral CNS architecture and might have represented an important event in the evolution of the vertebrate head. Current data suggest that the Otx2 replaced region and in particular the 3' untranslated region (UTR), may contain regulatory element(s) necessary to translate and/or stabilise Otx2 mRNA in epiblast and its derivatives.
|ISSN : ||0021-8782|
|Keywords : ||Otx,evolution,fore-midbrain,translational control,functional equivalence|