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PubMed2001

Apoptosis--a death-inducing mechanism tightly linked with morphogenesis in Hydractina echinata (Cnidaria, Hydrozoa).

Programmed cell death is not only known as a mechanism mediating tissue destruction, but also as an organismic tool for body shaping and regulation of morphological events during development. Here we report the tight and vital link of the most prominent form of programmed cell death, apoptosis, to one of the oldest, most basic, and most radical developmental processes, the metamorphosis of the marine hydrozoon Hydractinia echinata. Apoptosis, represented by DNA fragmentation, appears very early during metamorphosis, approximately 20 minutes post induction. It is then executed in a very distinct spatial and temporal pattern, including the removal or phagocytosis of a large number of larval cells prior to the appearance of stolons and tentacles. Our data indicate a developmental program striving to reduce all body parts that are no longer necessary, before reaching a distinct turning point, when the development of adult features is initiated. During these events, morphogenesis of basal and apical structures correlates with recycling of that particular larval region, indicated by the presence of apoptosis. Based on these data, the necessity of apoptosis for normal development of adult patterns is inferred and a fundamental association of apoptosis with developmental processes can be stated.

Animals↗

PubMed2000

The Myxococcus xanthus wbgB gene encodes a glycosyltransferase homologue required for lipopolysaccharide O-antigen biosynthesis.

Myxococcus xanthus is a gram-negative soil bacterium that initiates a complex developmental program in response to starvation. A transposon insertion (Tn5-lac omega109) mutant with developmental deficiencies was isolated and characterized in this study. A strain containing this insertion mutation in an otherwise wild-type background showed delayed developmental aggregation for about 12 h and sporulated at 1-2% of the wild-type level. Tn5-lac omega109 was found to have disrupted the M. xanthus wbgB gene, which is located 2.1 kb downstream of the M. xanthus lipopolysacharide (LPS) O-antigen biosynthesis genes wzm wzt wbgA. The deduced polypeptide sequence of WbgB shares significant similarity with bacterial glycosyltransferases including M. xanthus WbgA. The wbgB::Tn5-lac omega109 mutant was found to be defective in LPS O-antigen synthesis by immunochemical analysis. Further mutational analysis indicated that the defects of the wbgB::Tn5-lac omega109 mutant were not the result of polar effects on downstream genes. Various motility assays demonstrated that the Tn5-lac omega109 mutation affected both social (S) and adventurous (A) gliding motility of M. xanthus cells. The pleiotrophic effects of wbgB mutations indicate the importance of LPS O-antigen biosynthesis for various cellular functions in M. xanthus.

Amino Acid Sequence↗

PubMed1999

Dictyostelium ribosomal protein genes and the elongation factor 1B gene show coordinate developmental regulation which is under post-transcriptional control.

Starvation for amino acids initiates the developmental program in the cellular slime mold, Dictyostelium discoideum [19, 20]. One of the earliest developmental events is the decline in ribosomal protein synthesis [2, 17, 29, 30]. The ribosomal protein mRNAs are excluded from polysomes with 20 min to 1 h following the removal of nutrients, and their mRNA levels decline sharply at about 9 h into the 24-h developmental cycle [28, 31, 35, 36]. It has been generally assumed that the decline in r-protein mRNA levels during late development reflected a decline in the transcription rate [12, 32, 43]. Here we demonstrate that this is not the case. The transcription rates of three ribosomal protein genes, rpL11, rpL23 and rpS9 as well as an elongation factor 1B gene have been determined during growth and development in Dictyostelium. Throughout growth and development the transcription rate of the ribosomal protein genes remains relatively constant at 0.2%-0.5% of the rate of rRNA transcription while the elongation factor 1B gene is transcribed at 0.4%-0.6% of the rRNA rate. This low but constant transcription rate is in contrast to a spore coat protein gene Psp D, which is transcribed at 6% of the rRNA rate in late developing cells. The elongation factor 1B gene appears to be co-regulated with the ribosomal protein genes both in terms of its transcription rate and mRNA accumulation. Dictyostelium has been a popular model for understanding signal transduction and the growth to differentiation transition, thus it is of significance that the regulation of ribosome biosynthesis in Dictyostelium resembles that of higher eukaryotes in being regulated largely at the post-transcriptional level in response to starvation as opposed to yeasts where the regulation is largely transcriptional [27].

Amino Acid Sequence↗

PubMed2005

Enhancer-binding proteins with a forkhead-associated domain and the sigma54 regulon in Myxococcus xanthus fruiting body development.

In response to starvation, Myxococcus xanthus initiates a developmental program that results in the formation of spore-filled, multicellular fruiting bodies. Many developmentally regulated genes in M. xanthus are transcribed from sigma(54) promoters, and these genes require enhancer-binding proteins. Here we report the finding of an unusual group of 12 genes encoding sigma(54)-dependent enhancer-binding proteins containing a forkhead-associated (FHA) domain as their N-terminal sensory domain. FHA domains in other proteins recognize phosphothreonine residues. An insertion mutation in one of these genes, Mx4885, caused a cell autonomous aggregation and sporulation defect. In-frame deletion mutants showed that the FHA domain is necessary for proper Mx4885 function. The altered pattern of developmental gene expression in the mutant implied that Mx4885 is on the pathway of response to the morphogenetic C-signal. Immunoblots specific for C-signal and FruA imply that the site of Mx4885 action is downstream of FruA synthesis on the C-signal transduction pathway. Mx4885 may help to coordinate the level of intracellular phosphorylated FruA (FruA-P) with the level of C-signal displayed on the signal donor cell. Because FHA domains respond to phosphothreonine-containing proteins, these results suggest a regulatory link to the abundant Ser/Thr protein kinases in M. xanthus.

Amino Acid Sequence↗

PubMed1992

Replication-dependent and independent regulation of HMG expression during the cell cycle and conjugation in Tetrahymena.

Two abundant high-mobility-group (HMG)-like proteins, HMG B and HMG C, exist in the ciliated protozoan, Tetrahymena thermophila. Of these, HMG C is specific to transcriptionally active macronuclei, while HMG B is found in macronuclei and in transcriptionally inactive micronuclei [1]. Using Northern and in situ analyses, we show that the genes encoding HMG B and HMG C are not expressed uniformly throughout the vegetative cycle or during the sexual process, conjugation. Elevated expression of both genes is observed during macronuclear S phase of the vegetative cycle and during endoreplication of developing new macronuclei in later stages of conjugation. Interruption of any of these macronuclear DNA replications by aphidicolin leads to a rapid drop in the message levels of HMG B and HMG C. These results resemble what is typically observed for replication-dependent nucleosomal histones and differ from the apparent lack of cell cycle regulation observed for HMG genes in vertebrates. A specific-induction of HMG B mRNA is also observed early in conjugation and during this interval, inhibition of micronuclear DNA synthesis by aphidicolin does not affect the message level of HMG B. Thus, during conjugation, expression of HMG B shows both replication-dependent and independent regulation. Results similar to these with HMG B are obtained with histone H4II gene, a gene which is also expressed during micro- and macronuclear S phases during the vegetative cycle. These results demonstrate surprising complexity in the expression of HMG genes in Tetrahymena and lend support to the hypothesis that cell cycle regulation plays an important role in directing HMG-like proteins to the appropriate nucleus [2]. Interestingly, expression of neither HMG gene is perfectly synchronized with that of histone H4II gene during the developmental program suggesting that important differences exist between vegetatively growing (cell cycle control) and conjugating (developmental control) cells.

Animals↗

PubMed1991

Cells from Hertwig's epithelial root sheath do not transcribe amelogenin.

Recent experimental evidence has led to the interpretation that "enamel-like" material is deposited along the forming mouse molar root surface by cells of Hertwig's epithelial root sheath (HERS cells) and that this material is integral to the developmental program for cementogenesis. The experimental strategy described in this study was to examine selected developmental stages of root formation for mouse first and second mandibular molars in order to localize the cellular sites of amelogenin gene transcripts using high resolution in situ hybridization. Amelogenin is the major structural protein of coronal enamel and is highly conserved among mammalian species at the DNA and amino acid sequence level. Within the limits of sensitivity for in situ hybridization and utilizing either cRNAs or oligodeoxynucleotide probes, we were unable to localize amelogenin transcripts within HERS cells from selected developmental stages associated with mouse molar root formation. In contrast, previous studies using antipeptide antibodies have provided immuno-histochemical localization of amelogenin domains in HERS cell-derived products. For these HERS cell-derived proteins to contain both amelogenin epitopes and yet fail to yield nucleic acid hybridization signals suggests that either gene rearrangement and/or alternative processing of messenger RNAs from the structural gene locus operate to produce immunologically related motifs sharing insufficient complementarity at the nucleotide level to permit efficient detection by hybridization. It is postulated that HERS cells synthesize proteins which contain amelogenin domains and that these proteins participate during cementogenesis. However, these enamel-related proteins are neither identical to, nor collinear with coronal canonical amelogenin transcripts.

Ameloblasts↗

PubMed2003

EphA family gene expression in the developing mouse neocortex: regional patterns reveal intrinsic programs and extrinsic influence.

Parcellation of the mammalian cerebral cortex into distinct areas is essential for proper cortical function; however, the developmental program that results in the genesis of distinct areas is not fully understood. We examined the expression of members of the EphA family-the EphA receptor tyrosine kinases and the ephrin-A ligands-within the developing mouse cerebral cortex, with the aim of characterizing this component of the molecular landscape during cortical parcellation. We found that specific embryonic zones, such as the ventricular, subventricular, intermediate, subplate, and marginal zones, as well as the cortical plate, were positive for particular EphA genes early in corticogenesis (E12-E15). Along with this zone-selective expression, several genes (EphA3, EphA4, EphA5) were evenly expressed along the axes of the developing cortex, whereas one family member (EphA7) was expressed in a distinct anteroposterior pattern. Later in corticogenesis (E16-E18), other EphA family members became selectively expressed, but only within the cortical plate: EphA6 was present posteriorly, and ephrin-A5 was expressed within a middle region. At birth, patterning of EphA gene expression was striking. Thus, we found that the expression of a single EphA gene or a combination of family members can define distinct embryonic zones and anteroposterior regions of the neocortex during development. To examine whether cellular context affects the patterning of EphA expression, we examined gene expression in embryonic cortical cells grown in vitro, such that all cellular contacts are lacking, and in Mash-1 mutant mice, in which thalamocortical connections do not form. We found that the expression patterns of most EphA family members remained stable in these scenarios, whereas the pattern of ephrin-A5 was altered. Taken together, this work provides a comprehensive picture of EphA family expression during mouse corticogenesis and demonstrates that most EphA expression profiles are cell intrinsically based, whereas ephrin-A5 is plastically regulated.

Afferent Pathways↗

PubMed2006

Nonrestrictive developmental regulation of microRNA gene expression.

During different periods of mammalian development, global changes in gene expression occur. Developmental changes in global gene expression have been modeled as a restrictive process. To test the restriction model of global changes in gene expression, we have used embryonic stem (ES) cells as a model system for the early mammalian embryo. ES cells are pluripotent cells that can contribute to all cellular lineages of the developing mammalian fetus and are derived from early embryonic cells. Using this model system, we have studied a new class of RNAs called microRNAs that have been identified and shown to play a role in the direct regulation of messenger RNAs. Here we report the expression signature for 248 microRNAs in 13 independent murine ES cells, embryoid bodies, and somatic tissues. The expression profile for 248 mouse microRNAs was determined for embryonic stem cells, embryoid bodies, mouse embryos, mature heart, lung, liver, kidney, and brain. Characteristic microRNA expression signatures were observed for each evaluated sample. When the characteristic microRNA signatures for developmentally ordered samples were compared, immature samples exhibited a less complex microRNA transcript profile than did mature samples. Our data support a progressive model of microRNA gene expression. Based on the progressive increase in complexity of micro- RNA expression, we hypothesize that the mammalian developmental program requires a temporal coupling of expression between microRNAs and messenger RNAs to enable the developmental potential observed in mammalian ontogeny.

Animals↗

PubMed1987

Cancer genes, proto-oncogenes, and development.

The retroviral cancer genes have in a number of observations been shown to interfere with the developmental program of target cells. Here we are concerned with the interface between cancer genes/proto-oncogenes and developmental processes. Research in this field serves two purposes; to delineate key developmental controls and to identify these as targets for oncogenic agents.

Animals↗

PubMed2003

Temporal regulation of microRNA expression in Drosophila melanogaster mediated by hormonal signals and broad-Complex gene activity.

lin-4 and let-7 are founding members of an extensive family of genes that produce small transcripts, termed microRNAs (miRNAs). In Caenorhabditis elegans, lin-4 and let-7 control the timing of postembryonic events by translational repression of target genes, permitting progression from early to late developmental programs. To identify Drosophila melanogaster miRNAs that could play similar roles in the control of developmental timing, we characterized the developmental expression profile of 24 miRNAs in Drosophila, and found 7 miRNAs that are either upregulated or downregulated in conjunction with metamorphosis. The upregulation of three of these miRNAs (mir-100, mir-125, and let-7), and the downregulation of a fourth (mir-34) requires the hormone ecdysone (Ecd) and the activity of the Ecd-inducible gene Broad-Complex. Interestingly, mir-125 is a putative homologue of lin-4. mir-100, -125, and let-7 are clustered within an 800-bp region on chromosome 2L, suggesting that these three miRNAs may be coordinately regulated via common cis-acting elements during metamorphosis. In S2 cells, Ecd and the juvenile hormone analog methoprene exert opposite effects on the expression of these four miRNAs, indicating the participation of both these hormones in the temporal regulation of mir-34, -100, -125, and let-7 expression in vivo.

Animals↗

PubMed2002

Plant development meets cell proliferation in Madrid.

Cell division is intimately intertwined with plant development, and the mechanisms that link the control of cell proliferation and differentiation with the processes of organogenesis, morphogenesis, and growth are starting to be understood. A recent Juan March meeting explored this interface, and revealed a rich seam of exciting work that is leading toward an integrated view of the role of cell proliferation in the unfolding of developmental programs.

Cell Division↗

PubMedDate not supplied

Deuterostome evolution: early development in the enteropneust hemichordate, Ptychodera flava.

Molecular and morphological comparisons indicate that the Echinodermata and Hemichordata represent closely related sister-phyla within the Deuterostomia. Much less is known about the development of the hemichordates compared to other deuterostomes. For the first time, cell lineage analyses have been carried out for an indirect-developing representative of the enteropneust hemichordates, Ptychodera flava. Single blastomeres were iontophoretically labeled with Dil at the 2- through 16-cell stages, and their fates followed through development to the tornaria larval stage. The early cleavage pattern of P. flava is similar to that of the direct-developing hemichordate, Saccoglossus kowalevskii, as well as that displayed by indirect-developing echinoids. The 16-celled embryo contains eight animal "mesomeres," four slightly larger "macromeres," and four somewhat smaller vegetal "micromeres." The first cleavage plane was not found to bear one specific relationship relative to the larval dorsoventral axis. Although individual blastomeres generate discrete clones of cells, the appearance and exact locations of these clones are variable with respect to the embryonic dorsoventral and bilateral axes. The eight animal mesomeres generate anterior (animal) ectoderm of the larva, which includes the apical organ; however, contributions to the apical organ were found to be variable as only a subset of the animal blastomeres end up contributing to its formation and this varies from embryo to embryo. The macromeres generate posterior larval ectoderm, and the vegetal micromeres form all the internal, endomesodermal tissues. These blastomere contributions are similar to those found during development of the only other hemichordate studied, the direct-developing enteropneust, S. kowalevskii. Finally, isolated blastomeres prepared at either the two- or the four-cell stage are capable of forming normal-appearing, miniature tornaria larvae. These findings indicate that the fates of these cells and embryonic dorsoventral axial properties are not committed at these early stages of development. Comparisons with the developmental programs of other deuterostome phyla allow one to speculate on the conservation of some key developmental events/mechanisms and propose basal character states shared by the ancestor of echinoderms and hemichordates.

Animals↗

PubMed2005

Emergentism as a default: cancer as a problem of tissue organization.

During the last fifty years the dominant stance in experimental biology has been reductionism. For the most part, research programs were based on the notion that genes were in 'the driver's seat' controlling the developmental program and determining normalcy and disease (genetic reductionism and genetic determinism). Philosophers were the first to realize that the belief that the Mendelian genes were reduced to DNA molecules was questionable. Soon after these pronouncements, experimental data confirmed their misgivings. The optimism of molecular biologists, fueled by early success in tackling relatively simple problems, has now been tempered by the difficulties found when attempting to understand complex biological problems. Here, we analyse experimental data that illustrate the shortcomings of this sort of reductionism. We also examine the prevailing paradigm in cancer research, the somatic mutation theory (SMT), the premises of which are: (i) cancer is derived from a single somatic cell that has accumulated multiple DNA mutations; (ii) the default state of cell proliferation in metazoa is quiescence; and (iii) cancer is a disease of cell proliferation caused by mutations in genes that control proliferation and the cell cycle. We challenge the notion that cancer is a cellular problem caused by mutated genes by assessing data gathered both from within the reductionist paradigm and from an alternative view that regards carcinogenesis as a developmental process gone awry. This alternative view, explored under the name of the tissue organization field theory (TOFT), is based on premises that place cancer in a different hierarchical level of complexity from that proposed by the SMT, namely: (i) carcinogenesis represents a problem of tissue organization comparable to organogenesis, and (ii) proliferation is the default state of all cells. We propose that the organicist view, in which the TOFT is based, is a good starting point from which to explore emergent phenomena. However, new theoretical concepts are needed in order to grapple with the apparent circular causality of complex biological phenomena in development and carcinogenesis.

Animals↗

PubMed1994

DET1, a negative regulator of light-mediated development and gene expression in arabidopsis, encodes a novel nuclear-localized protein.

The mechanisms by which plants integrate light signals to modify endogenous developmental programs are largely unknown. One candidate for a signal transduction component that may integrate light with developmental pathways is the Arabidopsis DET1 gene product. Here we report the positional cloning of the DET1 locus and show that DET1 is a unique nuclear-localized protein. An analysis of a number of det1 mutants indicates that mutants with partial DET1 activity develop as light-grown plants in the dark. det1 null mutants share this phenotype, but also display severe defects in temporal and spatial regulation of gene expression. These results suggest that DET1 acts in the nucleus to control the cell type-specific expression of light-regulated promoters.

Amino Acid Sequence↗

PubMed2003

Molecular genetics of leaf senescence in Arabidopsis.

Leaf senescence is a developmentally programmed degeneration process that constitutes the final step of leaf development and is controlled by multiple developmental and environmental signals. In addition to the information obtained from other plants, Arabidopsis has, as a model system, contributed to our understanding of this complex phenomenon in molecular genetic terms. Recent discoveries have identified several genetic mutants and potential regulatory components in Arabidopsis. Identifying further mutants that exploit novel biological resources, screening Scheme and a global functional analysis of senescence-associated genes in Arabidopsis should increase our understanding of the complex regulatory networks.

Aging↗

PubMed2005

The developing limb and the control of the number of digits.

Congenital malformations of the limbs are among the most frequent congenital anomalies found in humans, and they preferentially affect the distal part--the hand or foot. The presence of extra digits, a condition called polydactyly, is the most common limb deformity of the human hand and is the consequence of disturbances in the normal program of limb development. However, despite the extensive use of the developing limb as a classical developmental model, the cellular and genetic mechanisms that control the number and identity of the digits are not completely understood. The aim of this review is to introduce the reader to the current state of knowledge in limb development and to provide the necessary background for an understanding of how deviations from the normal developmental program may lead to polydactyly.

Foot↗

PubMed2005

Balance between cell division and differentiation during plant development.

The processes which make possible that a cell gives rise to two daughter cells define the cell division cycle. In individual cells, this is strictly controlled both in time and space. In multicellular organisms extra layers of regulation impinge on the balance between cell proliferation and cell differentiation within particular ontogenic programs. In contrast to animals, organogenesis in plants is a post-embryonic process that requires developmentally programmed reversion of sets of cells from different differentiated states to a pluripotent state followed by regulated proliferation and progression through distinct differentiation patterns. This implies a fine coupling of cell division control, cell cycle arrest and reactivation, endoreplication and differentiation. The emerging view is that cell cycle regulators, in addition to controlling cell division, also function as targets for maintaining cell homeostasis during development. The mechanisms and cross talk among different cell cycle regulatory pathways are discussed here in the context of a developing plant.

Arabidopsis↗

PubMed2002

To die or not to die, does it change the function? Behavior of transgenic mice reveals a role for developmental cell death.

In humans, perturbations in the developmental neuronal death leading to an excess of neurons could be associated with developmental neuropsychiatric disorders. Hu-bcl-2 transgenic mice appear to be a valuable tool to study the functional role of developmental programmed cell death. Indeed, the over-expression of the anti-apoptotic gene bcl-2 decreases developmental neuronal death and Hu-bcl-2 mice present supernumerary neurons in several brain regions. A detailed behavioral analysis of these mice revealed selective deficits. Hu-bcl-2 mice have normal vision, general activity and motor skills. Only the most complex behavior like anxiety and learning abilities are impaired in these mice.

Animals↗