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PubMed2004

The expression of HSP83 genes in Leishmania infantum is affected by temperature and by stage-differentiation and is regulated at the levels of mRNA stability and translation.

BACKGROUND: Exposure of Leishmania promastigotes to the temperature of their mammalian hosts results in the induction of a typical heat shock response. It has been suggested that heat shock proteins play an important role in parasite survival and differentiation. RESULTS: Here we report the studies on the expression of the heat shock protein 83 (HSP83) genes of Leishmania infantum. Confirming previous observations for other Leishmania species, we found that the L. infantum HSP83 transcripts also show a temperature-dependent accumulation that is controlled by a post-transcriptional mechanism involving sequences located in the 3'-untranslated region (3'-UTR). However, contrary to that described for L. amazonensis, the accumulation of the HSP83 transcripts in L. infantum is dependent on active protein synthesis. The translation of HSP83 transcripts is enhanced during heat shock and, as first described in L. amazonensis, we show that the 3'-UTR of the L. infantum HSP83 gene is essential for this translational control. Measurement of the steady-state levels of HSP83 transcripts along the promastigote-to-amastigote differentiation evidenced a specific profile of HSP83 RNAs: after an initial accumulation of HSP83 transcripts observed short after (2 h) incubation in the differentiation conditions, the amount of HSP83 RNA decreased to a steady-state level lower than in undifferentiated promastigotes. We show that this transient accumulation is linked to the presence of the 3'-UTR and flanking regions. Again, an 8-fold increase in translation of the HSP83 transcripts is observed short after the initiation of the axenic differentiation, but it is not sustained after 9 h. CONCLUSIONS: This transient expression of HSP83 genes could be relevant for the differentiation of Leishmania, and the underlying regulatory mechanism may be part of the developmental program of this parasite.

3' Untranslated Regions↗

PubMed2005

Phosphorylation of c-Jun in avian and mammalian motoneurons in vivo during programmed cell death: an early reversible event in the apoptotic cascade.

c-Jun is a transcription factor that is involved in various cellular events, including apoptotic cell death. For example, phosphorylation of c-Jun is one of the earliest biochemical changes detected in dying sympathetic neurons after NGF deprivation in vitro. However, currently, it is not known whether a similar molecular event is involved in the developmental programmed cell death (PCD) of neurons in vivo. We observed that only a subpopulation of motoneurons (MNs) exhibit c-Jun phosphorylation during the PCD period in chick [embryonic day 5 (E5)-E12] and mouse (E13-E18) embryos. Experimental perturbation of MN survival-promoting signals by limb bud removal (reduced signals) or by activity blockade (increased signals) in the chick embryo demonstrated that the presence of those signals is negatively correlated with the number of c-Jun-phosphorylated MNs. This suggests that insufficient survival signals (e.g., neurotrophic factors) may induce c-Jun phosphorylation of MNs in vivo. Consistent with the idea that c-Jun phosphorylation is a reversible event during normal PCD of MNs, we found that c-Jun phosphorylation was transiently observed in a subpopulation of mouse MNs rescued from PCD by deletion of the proapoptotic gene Bax. Inhibition of c-Jun signaling significantly reduced MN death in chick embryo, indicating that activation of c-Jun signaling is necessary for the PCD of MNs. Together, c-Jun phosphorylation appears to be required for the initiation of an early and reversible event in the intracellular PCD cascade in vivo after loss of survival-promoting signals such as neurotrophic factors.

Animals↗

PubMed1999

Gene interactions in gonadal development.

The acquisition of a sexually dimorphic phenotype is a critical event in mammalian development. Although the maturation of sexual function and reproduction occurs after birth, essentially all of the critical developmental steps take place during embryogenesis. Temporally, these steps can be divided into two different phases: sex determination, the initial event that determines whether the gonads will develop as testes or ovaries; and sexual differentiation, the subsequent events that ultimately produce either the male or the female sexual phenotype. A basic tenet of sexual development in mammals is that genetic sex--determined by the presence or absence of the Y chromosome--directs the embryonic gonads to differentiate into either testes or ovaries. Thereafter, hormones produced by the testes direct the developmental program leading to male sexual differentiation. In the absence of testicular hormones, the pathway of sexual differentiation is female. This chapter reviews the anatomic and cellular changes that constitute sexual differentiation and discusses SRY and other genes, including SF-1, WT1, DAX-1, and SOX9, that play key developmental roles in this process. Dose-dependent interactions among these genes are critical for sex determination and differentiation.

Animals↗

PubMed2005

Transplantation of a polyembryonic wasp embryo: a technique for transferring endoparasitic embryo into the host egg.

Concealed development of many animal embryos prevents examination of development and limits the application of embryo manipulation techniques aimed at understanding developmental processes. In embryos developing in utero, such as in mammals, it is necessary to dissect embryos from the mother and, upon manipulative intervention, to implant them back into the recipient. Parasitic wasps present a promising system for understanding the evolution of early developmental processes. In basal ectoparasitic species that lay eggs on the surface of the host, it is possible to adapt embryo manipulation techniques developed in Drosophila. However, their derived endoparasitic relatives, which exhibit various modifications of developmental programs, undergo concealed development within the host body. For example, the parasitic polyembryonic wasp Copidosoma floridanum oviposits an egg into the egg of the host moth Trichoplusia ni. The host larva emerges and the parasite undergoes development within the host body, preventing embryo manipulation as a means of examining developmental regulation. Here we present a protocol for embryo transfer that allows the transplantation of C. floridanum egg into the host egg. This approach opens a new avenue in the application of various embryo manipulation techniques aimed at understanding the evolution of embryogenesis in endoparasitic Hymenoptera. In addition, this approach has potential for the development of other tools in C. floridanum, such as transgenesis and reverse genetics, which can also be extended to other endoparasitic species.

Animals↗

PubMed1990

Cell interactions in the sea urchin embryo studied by fluorescence photoablation.

In many organisms, interactions between cells play a critical role in the specification of cell fates. In the sea urchin embryo, primary mesenchyme cells (PMCs) regulate the developmental program of a subpopulation of secondary mesenchyme cells (SMCs). The timing of this cell interaction was analyzed by means of a fluorescence photoablation technique, which was used to specifically ablate PMCs at various stages of development. In addition, the PMCs were microinjected into PMC-depleted recipient embryos at different developmental stages and their effect on SMC fate was examined. The critical interaction between PMCs and SMCs was brief and took place late in gastrulation. Before that time, SMCs were insensitive to the suppressive signals transmitted by the PMCs.

Animals↗

PubMed1996

Alternative transcript of the chick alpha 2(I) collagen gene is transiently expressed during endochondral bone formation and during development of the central nervous system.

Endochondral bone formation is characterized by several transitions in the pattern of collagen gene expression, the best characterized of which occurs during chondrogenesis. Prechondrogenic mesenchymal cells synthesize predominantly type I collagen; during chondrogenesis, type I collagen synthesis ceases and production of cartilage-characteristic collagens is initiated. We previously identified the molecular mechanism that mediates cessation of alpha 2(I) collagen synthesis in chondrocytes (Bennett and Adams [1990] J. Biol. Chem. 265:2223-2230). This mechanism involves a change in the transcription initiation site, resulting in an alternative transcript that cannot encode alpha 2(I) collagen. In this report we demonstrate that the alternative transcript appears only transiently in cartilage. Its initial appearance is coincident with the onset of high levels of type II collagen synthesis in differentiated chondrocytes. However, it disappears in hypertrophic cartilage, and production of the authentic alpha 2(I) collagen mRNA is reinitiated, contributing to synthesis of a high level of type I collagen in hypertrophic chondrocytes at the chondro-osseous junction. We also show that the alternative transcript is not restricted to cartilage during embryonic development, since it initially appears in presomite embryos, well before the appearance of cartilage. At early stages of embryo-genesis the alternative transcript is restricted to tissues derived from neuroectoderm; its appearance in those tissues is also transient. These data suggest that production of the alternative transcript of the alpha 2(I) collagen gene may be required for cessation of alpha 2(I) collagen synthesis during chondrogenesis, but the alternative transcript may be involved in other important developmental programs as well.

Alternative Splicing↗

PubMed1995

Identification of a developmental timer regulating the stability of embryonic cyclin A and a new somatic A-type cyclin at gastrulation.

We have identified a second Xenopus cyclin A, called cyclin A2. Cyclin A2 is a 46.6-kD protein that shows a greater homology to human cyclin A than to the previously identified Xenopus cyclin A1. It is present throughout embryonic development (up to stage 46 at least) and is found in adult tissues as well as in Xenopus tissue culture cell lines. In contrast, cyclin A1 is present in eggs and early embryos but cannot be detected in late embryos or in tissue culture cells. We have found that the maternally stored pools of mRNAs encoding both of these cyclin A proteins are stable until the onset of gastrulation and then are degraded abruptly. At this time, new transcription replaces cyclin A2 mRNA. Interestingly, we have also observed a dramatic change in the stability of the cyclin A proteins at this time. Prior to the onset of gastrulation, cyclin A1 protein is stable during interphase of the cell cycle. At gastrulation, however, both A1 and A2 proteins turn over rapidly during interphase of the cell cycle. Together, these results indicate that developmental programs controlling cyclin A protein and mRNA stability are activated at gastrulation. We have shown that this program is independent of new transcription beginning at the mid-blastula transition. Furthermore, treatment of early stage embryos with cycloheximide demonstrates that activation of this degradative program is independent of cell division and translation. Collectively, our observations suggest that a previously uncharacterized timing mechanism activates new degradative pathways at the onset of gastrulation, which could play an essential role in releasing cells from maternal programming.

Amino Acid Sequence↗

PubMed1996

An intestine-specific homeobox gene regulates proliferation and differentiation.

Precise regulation of cellular proliferation, differentiation, and senescence results in the continuous renewal of the intestinal epithelium with maintenance of a highly ordered tissue architecture. Here we show that an intestine-specific homeobox gene, Cdx2, is a transcription factor that regulates both proliferation and differentiation in intestinal epithelial cells. Conditional expression of Cdx2 in IEC-6 cells, an undifferentiated intestinal cell line, led to arrest of proliferation for several days followed by a period of growth resulting in multicellular structures containing a well-formed columnar layer of cells. The columnar cells had multiple morphological characteristics of intestinal epithelial cells. Enterocyte-like cells were polarized with tight junctions, lateral membrane interdigitations, and well-organized microvilli with associated glycocalyx located at the apical pole. Remarkably, there were also cells with a goblet cell-like ultrastructure, suggesting that two of the four intestinal epithelial cell lineages may arise from IEC-6 cells. Molecular evidence for differentiation was shown by demonstrating that cells expressing high levels of Cdx2 expressed sucrase-isomaltase, an enterocyte-specific gene which is a well-defined target for the Cdx2 protein. Taken together, our data suggest that Cdx2 may play a role in directing early processes in intestinal cell morphogenesis and in the maintenance of the differentiated phenotype by supporting transcription of differentiated gene products. We propose that Cdx2 is part of a regulatory network that orchestrates a developmental program of proliferation, morphogenesis, and gene expression in the intestinal epithelium.

Animals↗

PubMed2005

Gene regulation in spermatogenesis.

Mammalian spermatogenesis is a complex hormone-dependent developmental program in which a myriad of events must take place to ensure that germ cells reach their proper stage of development at the proper time. Many of these events are controlled by cell type- and stage-specific transcription factors. The regulatory mechanisms involved provide an intriguing paradigm for the field of developmental biology and may lead to the development of new contraceptives an and innovative routs to treat male infertility. In this review, we address three aspects of the genetic regulatory mechanism that drive spermatogenesis. First, we detail what is known about how steroid hormones (both androgens and estrogens) and their cognate receptors initiate and maintain mammalian spermatogenesis. Steroids act through three mechanistic routes: (i) direct activation of genes through hormone-dependent promoter elements, (ii) secondary transcriptional responses through activation of hormone-dependent transcription factors, and (iii) rapid, transcription-independent (nonclassical) events induced by steroid hormones. Second, we provide a survey of transcription factors that function in mammalian spermatogenesis, including homeobox, zinc-finger, heat-shock, and cAMP-response family members. Our survey is not intended to cover all examples but to give a flavor for the gamut of biological roles conferred by transcription factors in the testis, particularly those defined in knockout mice. Third, we address how testis-specific transcription is achieved. In particular, we cover the evidence for and against the idea that some testis-specific genes are transcriptionally silent in somatic tissues as a result of DNA methylation.

Animals↗

PubMed2002

Ecological regulation of development: induction of marine invertebrate metamorphosis.

In the marine environment a wide range of invertebrates have a pelagobenthic lifecycle that includes planktonic larval and benthic adult phases. Transition between these morphologically and ecologically distinct phases typically occurs when the developmentally competent larva comes into contact with a species-specific environmental cue. This cue acts as a morphogenetic signal that induces the completion of the postlarval/juvenile/adult developmental program at metamorphosis. The development of competence often occurs hours to days after the larva is morphologically mature. In the non-feeding--lecithotrophic--larvae of the ascidian Herdmania curvata and the gastropod mollusc Haliotis asinina, gene expression patterns in pre-competent and competent stages are markedly different, reflecting the different developmental states of these larval stages. For example, the expression of Hemps, an EGF-like signalling peptide required for the induction of Herdmania metamorphosis, increases in competent larvae. Induction of settlement and metamorphosis results in further changes in developmental gene expression, which apparently is necessary for the complete transformation of the larval body plan into the adult form.

Animals↗

PubMed2002

An ovarian follicular epithelium protein of the silkworm (Bombyx mori) that associates with the vitelline membrane and contributes to the structural integrity of the follicle.

We have cloned and functionally characterized a novel protein, BmVMP30, which is synthesized by the cells of the follicular epithelium of the ovarian follicles of the domesticated silkworm Bombyx mori, secreted from them and associated with the vitelline membrane. BmVMP30 is a 30 kDa protein that bears limited structural features reminiscent of other insect vitelline membrane proteins. Although BmVMP30 does not share pronounced similarities or signature motifs with other reported proteins, its temporal and spatial expression and its behavior throughout oogenesis suggest that it is a novel member of the insect vitelline membrane protein family. The protein is expressed exclusively in the cells of the follicular epithelium during stages -15 to -1 of vitellogenesis, secreted from them and, ultimately, localized at the junction between the oocyte and the eggshell, where the vitelline membrane is located. Treatment of follicles with an antisense oligonucleotide that encompasses the translation initiation codon results in the production of an N-terminally truncated protein and disruption of the integrity of the follicular epithelium. Antisense oligonucleotide treatment, however, has no effect on the implementation of the developmental program that directs the autonomous progression of ovarian follicles through the last stages of vitellogenesis and choriogenesis.

Animals↗

PubMed2000

Pax7 is required for the specification of myogenic satellite cells.

The paired box transcription factor Pax7 was isolated by representational difference analysis as a gene specifically expressed in cultured satellite cell-derived myoblasts. In situ hybridization revealed that Pax7 was also expressed in satellite cells residing in adult muscle. Cell culture and electron microscopic analysis revealed a complete absence of satellite cells in Pax7(-/-) skeletal muscle. Surprisingly, fluorescence-activated cell sorting analysis indicated that the proportion of muscle-derived stem cells was unaffected. Importantly, stem cells from Pax7(-/-) muscle displayed almost a 10-fold increase in their ability to form hematopoietic colonies. These results demonstrate that satellite cells and muscle-derived stem cells represent distinct cell populations. Together these studies suggest that induction of Pax7 in muscle-derived stem cells induces satellite cell specification by restricting alternate developmental programs.

Age Factors↗

PubMed2002

Transcriptional regulation of a rice mitogen-activated protein kinase gene, OsMAPK4, in response to environmental stresses.

Mitogen-activated protein kinase (MAPK) cascades play important roles in signal transduction of extracellular stimuli in eukaryotes. However, stimulatory signals for plant MAPKs have not been well elucidated. Here, a cDNA clone, termed Oryza sativa MAPK4 (OsMAPK4), from rice encoding a protein that showed homology with the eukaryotic MAPKs was isolated. According to the phylogenetic analysis, OsMAPK4 belongs to subgroup IV MAPK in plants. OsMAPK4 transcripts were expressed strongly in mature leaves and weakly in young leaves and panicles. The gene was also differentially expressed in roots at different developmental stages. In addition, the mRNA level of OsMAPK4 was up-regulated under sugar starvation, high salinity and cold treatments. These results suggest that this OsMAPK4 functions not only in developmental programs but also in stress-signaling pathways.

Amino Acid Sequence↗

PubMed2004

Trends in antimicrobial drug development: implications for the future.

The need for new antimicrobial agents is greater than ever because of the emergence of multidrug resistance in common pathogens, the rapid emergence of new infections, and the potential for use of multidrug-resistant agents in bioweapons. Paradoxically, some pharmaceutical companies have indicated that they are curtailing anti-infective research programs. We evaluated the United States Food and Drug Administration (FDA) databases of approved drugs and the research and development programs of the world's largest pharmaceutical and biotechnology companies to document trends in the development of new antimicrobial agents. FDA approval of new antibacterial agents decreased by 56% over the past 20 years (1998-2002 vs. 1983-1987). Projecting future development, new antibacterial agents constitute 6 of 506 drugs disclosed in the developmental programs of the largest pharmaceutical and biotechnology companies. Despite the critical need for new antimicrobial agents, the development of these agents is declining. Solutions encouraging and facilitating the development of new antimicrobial agents are needed.

Anti-Bacterial Agents↗

PubMed1987

Molecular cloning and genetic analysis of the suppressor-of-white-apricot locus from Drosophila melanogaster.

We report genetic and molecular analysis of the suppressor-of-white-apricot [su(wa)] locus, one of several retrotransposon insertion allele-specific suppressor loci in Drosophila melanogaster. First, we isolated and characterized eight new mutations allelic to the original su(wa)1 mutation. These studies demonstrated that su(wa) mutations allelic to su(wa)1 affected a conventional D. melanogaster complementation group. Second, we cloned the chromosomal region containing the su(wa) complementation group by P element transposon tagging. The ca. 14-kilobase region surrounding the su(wa) complementation group contained five distinct transcription units, each with a different developmentally programmed pattern of expression. Third, we used a modified procedure for P-mediated gene transfer to identify the transcription unit corresponding to su(wa) by gene transfer. Fourth, we found that the presumptive su(wa) transcription unit produced a family of transcripts (ranging from ca. 3.5 to ca. 5.2 kilobases) in all developmental stages, tissue fractions, and cell lines we examined, suggesting that the gene is universally expressed.

Animals↗

PubMed1997

Misexpression of nautilus induces myogenesis in cardioblasts and alters the pattern of somatic muscle fibers.

nautilus (nau), one member of the myogenic regulatory family of bHLH-encoding genes, is expressed in a subset of muscle precursors and differentiated fibers in the Drosophila embryo. To elucidate the role of nautilus in myogenesis, we have misexpressed it using the GAL4-targeted system. We find that ectopic expression results in lethality throughout Drosophila development. We analyzed the effects of embryonic expression in mesodermal tissues that include the cardioblasts of the dorsal vessel as well most, if not all, of the presumptive somatic muscle precursors. Immunohistochemical staining for muscle MHC revealed abnormalities that include an absence of cardial cells, coincident with the appearance of novel muscle fibers adjacent to the dorsal vessel. Moreover, many cardioblasts express increased levels of muscle-specific genes such as myosin, actin 57B, and Mlp60A, a protein that is restricted to the somatic, visceral, and pharyngeal muscles. These data suggest that the missing cardial cells have been transformed into cells with properties similar to those of the somatic muscles. In addition, ubiquitous expression of nautilus in somatic muscle cells of these embryos resulted in muscle pattern defects. Specifically, muscles that do not normally express nautilus were frequently absent, and novel fibers were observed in positions reminiscent of nau-expressing muscles. These data imply that nautilus can alter the developmental program of muscle precursors. In summary, we suggest that nautilus induces myogenic differentiation in vivo when ectopically expressed in developing cardioblasts and may affect the myogenic differentiation program of specific muscle fibers.

Animals↗

PubMed1999

Developmentally regulated telomerase activity is correlated with chromosomal healing during chromatin diminution in Ascaris suum.

Telomerase is the ribonucleoprotein complex responsible for the maintenance of the physical ends, or telomeres, of most eukaryotic chromosomes. In this study, telomerase activity has been identified in cell extracts from the nematode Ascaris suum. This parasitic nematode is particularly suited as a model system for the study of telomerase, because it shows the phenomenon of chromatin diminution, consisting of developmentally programmed chromosomal breakage, DNA elimination, and new telomere formation. In vitro, the A. suum telomerase is capable of efficiently recognizing and elongating nontelomeric primers with nematode-specific telomere repeats by using limited homology at the 3' end of the DNA to anneal with the putative telomerase RNA template. The activity of this enzyme is developmentally regulated, and it correlates temporally with the phenomenon of chromatin diminution. It is up-regulated during the first two rounds of embryonic cell divisions, to reach a peak in 4-cell-stage embryos, when three presomatic blastomeres prepare for chromatin diminution. The activity remains high until the beginning of gastrulation, when the last of the presomatic cells undergoes chromatin diminution, and then constantly decreases during further development. In summary, our data strongly argue for a role of this enzyme in chromosome healing during the process of chromatin diminution.

Animals↗

PubMed2002

Involvement of a matrix metalloproteinase in MIS-induced cell death during urogenital development.

Programmed cell death of the Müllerian duct eliminates the primitive female reproductive tract during normal male sexual differentiation. Müllerian inhibiting substance (MIS or AMH) triggers regression by propagating a BMP-like signaling pathway in the Müllerian mesenchyme that culminates in apoptosis of the Müllerian duct epithelium. Presently, the paracrine signal(s) used in this developmental event are undefined. We have identified a member of the matrix metalloproteinase gene family, Mmp2, as one of the first candidate target genes downstream of the MIS cascade to function as a paracrine death factor in Müllerian duct regression. Consistent with a role in regression, Mmp2 expression was significantly elevated in male but not female Müllerian duct mesenchyme. Furthermore, this sexually dimorphic expression of Mmp2 was extinguished in mice lacking the MIS ligand, suggesting strongly that Mmp2 expression is regulated by MIS signaling. Using rat organ genital ridge organ cultures, we found that inhibition of MMP2 activity prevented MIS-induced regression, whereas activation of MMP2 promoted ligand-independent Müllerian duct regression. Finally, MMP2 antisense experiments resulted in partial blockage of Müllerian duct regression. Based on our findings, we propose that similar to other developmental programs where selective elimination or remodeling of tissues occurs, localized induction of extracellular proteinases is critical for normal male urogenital development.

Animals↗