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PubMed2005

Conserved sequences and the evolution of gene regulatory signals.

Studies of evolutionary conservation of gene regulatory signals have led to a paradox: extensive sequence similarity implies functional conservation in non-coding regions across mammalian species; however, this stands in contrast to our understanding of transcriptional regulatory sites composed of degenerate recognition sequences for transcription factors that can maintain functional equivalence despite considerable sequence divergence. The latter observation provides an explanation for the rapid evolution of new traits through the gain and loss of transcription factor binding sites that bring new genes under the control of an existing genetic regulatory network. The former observation might point to novel mechanisms of gene regulation and/or chromosome function that are currently unappreciated. Recent comparative genome analysis has highlighted extensive conserved sequences in mammalian genomes that are beginning to be functionally characterized.

Animals↗
PubMed2001

MADS-box genes are involved in floral development and evolution.

MADS-box genes encode transcription factors in all eukaryotic organisms thus far studied. Plant MADS-box proteins contain a DNA-binding (M), an intervening (I), a Keratin-like (K) and a C-terminal C-domain, thus plant MADS-box proteins are of the MIKC type. In higher plants most of the well-characterized genes are involved in floral development. They control the transition from vegetative to generative growth and determine inflorescence meristem identity. They specify floral organ identity as outlined in the ABC model of floral development. Moreover, in Antirrhinum majus the MADS-box gene products DEF/GLO and PLE control cell proliferation in the developing flower bud. In this species the DEF/GLO and the SQUA proteins form a ternary complex which determines the overall "Bauplan" of the flower. Phylogenetic reconstructions of MADS-box sequences obtained from ferns, gymnosperms and higher eudicots reveal that, although ferns possess already MIKC type genes, these are not orthologous to the well characterized MADS-box genes from gymnosperms or angiosperms. Putative orthologs of floral homeotic B- and C-function genes have been identified in different gymnosperms suggesting that these genes evolved some 300-400 million years ago. Both gymnosperms and angiosperms also contain a hitherto unknown sister clade of the B-genes, which we termed Bsister. A novel hypothesis will be described suggesting that B and Bsister might be involved in sex determination of male and female reproductive organs, respectively.

Evolution, Molecular↗
PubMed2000

Interplay between liganded and orphan nuclear receptors controls reproductive pathways.

Nuclear receptors are transcription factors that belong to an evolutionary ancient superfamily. These proteins, which are even present in primitive metazoans, are implicated in all levels of cell fate: proliferation, differentiation, and apoptosis. Some of these nuclear receptors behave as ligand-inducible transcription factors, as they have acquired during evolution the ability to bind ligands. This is the case for some proteins that recognize small hydrophobic signaling molecules, and particularly the estrogen receptor (ER or NR3A1), which regulates the target gene's transcription rate under estrogen binding. It is now known that the ER alone regulates the transcription of many genes, such as those implicated in reproductive functions. However, this ER-mediated signaling pathway could be modulated by other transcription factors. Our work has established that two other orphan nuclear receptors (SF-1 or NR5A1 and the COUP-TFs, NR2F1 and NR2F2) can enhance two ER-regulated genes implicated in salmonid reproductive functions: the ER gene itself, and the sGTHIIbeta gene. Moreover, some xenoestrogens could disturb these regulations. Therefore, our data contribute to the concept that interplay between nuclear receptors is an important event for the transcriptional regulation of genes controlling cellular functions.

Animals↗
PubMedDate not supplied

Ectoderm- and endomesoderm-specific GATA transcription factors in the marine annelid Platynereis dumerilli.

The GATA family of transcription factors appears to retain conserved roles in early germ layer patterning in most, if not all, animals; however, the number and structure of GATA factor genes varies substantially when different animal genomes are compared. Thus, the origin and relationships of invertebrate and vertebrate GATA factors, and their involvement in animal germ layer evolution, are unclear. We identified two highly conserved GATA factor genes in a marine annelid, the polychaete Platynereis dumerilii. A phylogenetic analysis indicates that the two Platynereis GATA factors are orthologous to the GATA1/2/3 and GATA4/5/6 subfamilies present in vertebrates. We also identified conserved motifs within each GATA class, and assigned the divergent Caenorhabditiselegans and Drosophila melanogaster GATA factor genes to the vertebrate classes. Similar to their vertebrate homologs, PdGATA123 mRNA expression was restricted to ectoderm, whereas PdGATA456 was detected only in endomesoderm. Finally, we identified in genome databases one GATA factor gene in each of two distantly related cnidarians that include motifs from both bilaterian GATA factor classes. Our results show that distinct orthologs of the two vertebrate GATA factor classes exist in a protostome invertebrate, suggesting that bilaterian GATA factors originated from GATA1/2/3 and 4/5/6 ancestral orthologs. Moreover, our results indicate that the GATA gene duplication and the functional divergence that led to these two ancestral GATA factor genes occurred after the split of the bilaterian stem group from the cnidarians.

Animals↗
PubMed2002

Expression pattern, regulation, and biological role of runt domain transcription factor, run, in Caenorhabditis elegans.

The Caenorhabditis elegans run gene encodes a Runt domain factor. Runx1, Runx2, and Runx3 are the three known mammalian homologs of run. Runx1, which plays an essential role in hematopoiesis, has been identified at the breakpoint of chromosome translocations that are responsible for human leukemia. Runx2 plays an essential role in osteogenesis, and inactivation of one allele of Runx2 is responsible for the human disease cleidocranial dysplasia. To understand the role of run in C. elegans, we used transgenic run::GFP reporter constructs and a double-stranded RNA-mediated interference method. The expression of run was detected as early as the bean stage exclusively in the nuclei of seam hypodermal cells and lasted until the L3 stage. At the larval stage, expression of run was additionally detected in intestinal cells. The regulatory elements responsible for the postembryonic hypodermal seam cells and intestinal cells were separately located within a 7.2-kb-long intron region. This is the first report demonstrating that an intron region is essential for stage-specific and cell type-specific expression of a C. elegans gene. RNA interference analysis targeting the run gene resulted in an early larva-lethal phenotype, with apparent malformation of the hypodermis and intestine. These results suggest that run is involved in the development of a functional hypodermis and gut in C. elegans. The highly conserved role of the Runt domain transcription factor in gut development during evolution from nematodes to mammals is discussed.

Animals↗
PubMed2000

Increased cell death and delayed development in the cerebellum of mice lacking the rev-erbA(alpha) orphan receptor.

The rev-erbA(alpha) gene, belonging to the steroid receptor superfamily of transcription factors, is highly conserved during evolution but little is known so far about its functions in development or in adult physiology. Here, we describe genetically altered mice lacking the rev-erbA(alpha) gene. These animals do not show any obvious phenotype in either fat tissue or skeletal muscle, despite the known regulation of rev-erbA(alpha) expression during adipocyte and myotube differentiation in vitro. However, during the second week of life, the cerebellum of rev-erbA(alpha) mutants presents several unexpected abnormalities, such as alterations in the development of Purkinje cells, delay in the proliferation and migration of granule cells from the external granule cell layer and increased apoptosis of neurons in the internal granule cell layer. Interestingly, the expression pattern of rev-erbA(alpha) suggests that the abnormalities observed in the external granule cell layer could be secondary to Purkinje cell alterations. Taken together, our data underline the importance of rev-erbA(alpha)expression for the appropriate balance of transcriptional activators and repressors during postnatal cerebellar development.

Animals↗
PubMed1991

A protein domain conserved between yeast MCM1 and human SRF directs ternary complex formation.

MCM1 and SRF bind to the same DNA sequence and form ternary complexes with STE12 and p62TCF, respectively. We show that in gel retardation assays, MCM1 recruits both ternary complex factors whereas SRF interacts only with p62TCF. A protein domain of 90 amino acids, shared by MCM1 and SRF, was found to be sufficient for ternary complex formation. The domain is also required for dimerization and DNA binding. Similar regions are found in other proteins, such as ARG80, Deficiens and Agamous. ARG80 and Agamous exhibit similar DNA binding specificities but do not interact with either STE12 or p62TCF. By exchanging three residues of ARG80 with those of corresponding positions in SRF (residues 198, 200 and 203), the ARG80 protein acquires the ability to recruit p62TCF into a ternary complex. Likewise, the substitution of four SRF amino acids by MCM1-derived residues (amino acids 73, 75, 77 and 78) confers on SRF the ability to interact with STE12. Thus, we have identified specific amino acids in MCM1 and SRF that are critical for ternary complex formation and which map to equivalent positions within the shared domains. Therefore, the structural basis for specific protein-protein interaction appears to be conserved in evolution between a class of transcription factors.

Amino Acid Sequence↗
PubMedDate not supplied

Major regulatory factors in the evolution of development: the roles of goosecoid and Msx in the evolution of the direct-developing sea urchin Heliocidaris erythrogramma.

The transcription factors Gsc and Msx are expressed in the oral ectoderm of the indirect-developing sea urchin Heliocidaris tuberculata. Their patterns of expression are highly modified in the direct developer Heliocidaris erythrogramma, which lacks an oral ectoderm. We here test the hypothesis that they are large effect genes responsible for the loss of the oral ectoderm module in the direct-developing larva of H. erythrogramma as well as for the restoration of an overt oral ectoderm in H.e. xH.t. hybrids. We undertook misexpression/overexpression and knockdown assays in the two species and in hybrids by mRNA injection. The results indicate that dramatic changes of function of these transcription factors has occurred. One of these genes, Gsc, has the ability when misexpressed to partially restore oral ectoderm in H. erythrogramma. On the other hand, Msx has lost any oral function and instead has a role in mesoderm proliferation and patterning. In addition, we found that the H. tuberculataGsc is up regulated in H.e. xH.t. hybrids, showing a preferential use of the indirect developing parental gene in the development of the hybrid. We suggest that Gsc qualifies as a gene of large evolutionary effect and is partially responsible for the evolution of direct development of H. erythrogramma. We discuss these results in light of modularity and genetic networks in development, as well as in their implications for the rapid evolution of large morphological changes in development.

Animals↗
PubMed2003

Role of AML1/Runx1 in the pathogenesis of hematological malignancies.

AML1/Runx1, originally identified as a gene located at the breakpoint of the t(8;21) translocation, encodes one of the two subunits forming a heterodimeric transcription factor. AML1 contains a highly evolutionally conserved domain called the Runt domain, responsible for both DNA binding and heterodimerization with the partner protein, CBFbeta. AML1 is widely expressed in all hematopoietic lineages, and regulates the expression of a variety of hematopoietic genes. Numerous studies have shown that AML is a critical regulator of hematopoietic development. In addition, AML1 and CBFbeta are frequent targets for chromosomal translocation in human leukemia. Translocations lead to the generation of fusion proteins, which play a causative role for the development of leukemia, primarily by inhibiting AML1 function. Point mutations that impair AML1 function are also associated with familial and sporadic leukemias. Loss of AML1 function is thus implicated in a number of leukemias through multiple pathogenic mechanisms. However, AML1-related translocations or haploinsufficiency of AML1 are not immediately leukemogenic in animal models, suggesting that additional genetic events are required for the development of full-blown leukemia.

Animals↗
PubMed2003

Structure, evolution and expression of the FOXL2 transcription unit.

FOXL2 is a putative transcription factor involved in ovarian development and function. Its mutations in humans are responsible for the blepharophimosis syndrome, characterized by eyelid malformations and premature ovarian failure (POF). Here we have performed a comparative sequence analysis of FOXL2 sequences of ten vertebrate species. We demonstrate that the entire open reading frame (ORF) is under purifying selection leading to strong protein conservation. We also review recent data on FOXL2 transcript and protein expression. FOXL2 has been shown 1) to be the earliest known sex dimorphic marker of ovarian determination/differentiation in vertebrates, 2) to have, at least in mammals, an ovarian expression persisting until adulthood. The conservation of its sequence and pattern of expression suggests that FOXL2 might be a key factor in the early development of the vertebrate female gonad and involved later in adult ovarian function. Finally, we provide arguments for the existence of an alternative transcript in rodents, that may arise from a differential polyadenylation. Although it has only been demonstrated in rodents, its presence/absence in other species deserves further investigation.

Amino Acid Sequence↗
PubMed2005

Variation in positive selection in termite GNBPs and Relish.

Social insects are model organisms for investigating molecular evolution in the innate immune system. Their diversity affords comparative analysis among closely related species, and group living is likely to contribute to the pathogen stress imposed on the immune system. We used different models of nucleotide substitution at nonsynonymous (amino acid altering) and synonymous (silent) sites to compare the different levels and type of selection among three immunity genes in 13 Australian termite species (Nasutitermes). The immunity genes include two encoding pathogen recognition proteins (gram-negative bacterial-binding proteins) that duplicated and diverged before or soon after the evolution of the termites and a transcription factor (Relish), which induces the production of antimicrobial peptides. A comparison of evolutionary models that assign four unrestricted classes of dN/dS (the ratio of the nonsynonymous to synonymous substitution rate) to different Nasutitermes lineages revealed that the occurrence of positive selection (dN/dS > 1) varies among lineages and the three genes. Positive selection appears to have driven the evolution of all three genes in an ancestral lineage of three subterranean termites. It had previously been suggested that there was a transition along this ancestral lineage to termite morphology and ecology associated with a diet of decayed wood, a diet that may expose termites to elevated levels of fungal and bacterial pathogens. Relish appears to have experienced the highest levels of selective pressure for change among all three genes. Positively selected sites in the molecule are located in regions that are important for its activation, which suggests that amino acid substitutions at these sites are a counter response to pathogen mechanisms that disrupt the activation of Relish.

Amino Acid Substitution↗
PubMed2004

Evolution of eukaryotic transcription: insights from the genome of Giardia lamblia.

The Giardia lamblia genome sequencing project affords us a unique opportunity to conduct comparative analyses of core cellular systems between early and late-diverging eukaryotes on a genome-wide scale. We report a survey to identify canonical transcription components in Giardia, focusing on RNA polymerase (RNAP) subunits and transcription-initiation factors. Our survey revealed that Giardia contains homologs to 21 of the 28 polypeptides comprising eukaryal RNAPI, RNAPII, and RNAPIII; six of the seven RNAP subunits without giardial homologs are polymerase specific. Components of only four of the 12 general transcription initiation factors have giardial homologs. Surprisingly, giardial TATA-binding protein (TBP) is highly divergent with respect to archaeal and higher eukaryotic TBPs, and a giardial homolog of transcription factor IIB was not identified. We conclude that Giardia represents a transition during the evolution of eukaryal transcription systems, exhibiting a relatively complete set of RNAP subunits and a rudimentary basal initiation apparatus for each transcription system. Most class-specific RNAP subunits and basal initiation factors appear to have evolved after the divergence of Giardia from the main eukaryotic line of descent. Consequently, Giardia is predicted to be unique in many aspects of transcription initiation with respect to paradigms derived from studies in crown eukaryotes.

Animals↗
PubMed1993

Hox homeobox genes and regionalisation of the nervous system.

The Hox family of homeobox-containing genes are intimately associated with the processes of axial patterning in vertebrate embryos. This family of transcription factors is widely conserved in evolution and by analogy with their Drosophila counterparts, the HOM-C homeotic genes, may play a role in establishing regional identity in a number of embryonic systems, including the CNS. The patterns of expression of these genes are linked with the generation of rhombomeres and neural crest in the developing hindbrain, and suggest that they provide a molecular system for generating a combinatorial patterning mechanism. Analysis of mouse Hox mutants generated by homologous recombination have clearly demonstrated that the genes have important roles in normal regionalisation of the hindbrain and branchial arches, and this has lead to interest in how their early patterns are established in the nervous system. The Hox genes and their relation to hindbrain segmentation therefore provide a means of examining the cascade of events which regulates pattern formation in early neural development.

Animals↗
PubMed1998

Cloning, mapping, and expression analysis of TBX15, a new member of the T-Box gene family.

The T-box gene family has been conserved throughout metazoan evolution and codes for putative transcription factors that share a uniquely defining DNA-binding domain. We have previously uncovered six mouse T-box genes with discrete spatial and temporal patterns of expression during embryogenesis. Here, we report a novel mouse T-box gene, Tbx15. The Tbx15 gene produces a 3.7-kb transcript with an open reading frame coding for a polypeptide with 602 amino acid residues. Phylogenetic analysis places the Tbx15 gene into a T-box subfamily that also includes mouse Tbx1, Drosophila H15, and nematode Ce-tbx-12 genes. We have mapped mouse Tbx15 to chromosome 3, at a position 49 cM from the centromere. During development, Tbx15 transcripts are first detected at embryonic day 9.5. The gene is expressed primarily in the cranio-facial region and in the developing limbs. An isolated human homolog, TBX15, has been mapped by in situ hybridization to chromosomal band 1p13. TBX15 appears to be an excellent candidate for the dominantly expressed acromegaloid facial appearance syndrome, which also maps to the short arm of human chromosome 1 and, like TBX15, is expressed prominently in the eyebrow regions.

Animals↗
PubMed2006

Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network.

In multicellular organisms, the ability to regulate reproduction, development, and nutrient utilization coincided with the evolution of nuclear receptors (NRs), transcription factors that utilize lipophilic ligands to mediate their function. Studying the expression profile of NRs offers a simple, powerful way to obtain highly relational information about their physiologic functions as individual proteins and as a superfamily. We surveyed the expression of all 49 mouse NR mRNAs in 39 tissues, representing diverse anatomical systems. The resulting data set uncovers several NR clades whose patterns of expression indicate their ability to coordinate the transcriptional programs necessary to affect distinct physiologic pathways. Remarkably, this regulatory network divides along the following two physiologic paradigms: (1) reproduction, development, and growth and (2) nutrient uptake, metabolism, and excretion. These data reveal a hierarchical transcriptional circuitry that extends beyond individual tissues to form a meganetwork governing physiology on an organismal scale.

Animals↗
PubMed2000

The expression of nonchordate deuterostome Brachyury genes in the ascidian Ciona embryo can promote the differentiation of extra notochord cells.

The notochord is a structure present in all chordates and its development requires the transcription of Brachyury. While previous studies have shown that Brachyury is essential for notochord formation in vertebrate embryos, this gene is also expressed during the embryogenesis of nonchordate deuterostomes, hemichordates and echinoderms. Here we report that nonchordate deuterostome Brachyury genes can trigger the differentiation of extra notochord cells when these genes are ectopically expressed in ascidian embryos. The 2.6 kb upstream region of fork head gene (Ci-fkh) of Ciona intestinalis promotes the tissue-specific expression of a reporter gene in endoderm, notochord and nerve cord. By taking advantage of this promoter, we misexpressed the Brachyury gene of ascidian (Ci-Bra), cephalochordate amphioxus (Am(Bb)Bra2), hemichordate acorn worm (PfBra), and echinoderm sea urchin (SpBra), in Ciona embryos. The misexpression of not only the chordate Brachyury, but also the nonchordate deuterostome Brachyury, resulted in the transformation of presumptive endodermal cells into notochord cells. This was confirmed by in situ hybridization experiments using four different notochord-specific probes from Ciona that have different temporal expression patterns. RT-PCR analyses indicated that Ci-Bra was not upregulated by the product of Am(Bb)Bra2, PfBra or SpBra. In situ hybridization showed no ectopic expression of Ci-Bra in the manipulated embryos. These results suggest that the introduction of nonchordate deuterostome Brachyury genes into ascidian embryos can trigger the differentiation of notochord cells in ascidian embryos. Evolutionary alteration in the genetic circuitry, especially downstream of this transcription factor, seems critical for the evolution of notochord and chordate body plan.

Amino Acid Sequence↗
PubMed2002

Expression of a novel TGIF subclass homeobox gene, Tex1, in the spermatids of mouse testis during spermatogenesis.

The homeobox gene superfamily is highly conserved during evolution. These genes act as transcription factors during several important developmental processes through their 60 amino acid homeodomains that recognize and bind to the regulatory region of their target genes. We isolated a novel homeobox gene designated Tex1 from a mouse testis cDNA library by degenerate oligonucleotide polymerase chain reaction (PCR) screening. Three extra amino acid residues, AYP, are inserted between the first and second helices of the homeodomain, which makes Tex1 a TGIF subclass homeobox gene. Tex1 was expressed specifically in the testis as seen by both Northern blot and RT-PCR analysis. Tex1 expression is initiated at around day 20 of testes. Furthermore, the results of in situ hybridization analysis reveal that the expression of Tex1 in testis is restricted in the germ cells at spermatid stage. Based on these data, it is suggested that Tex1, a novel testis homeobox gene, may play a crucial role during spermatogenesis.

Amino Acid Sequence↗