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PubMed2001

Regulation of plant growth by cytokinin.

Cytokinins are a class of plant-specific hormones that play a central role during the cell cycle and influence numerous developmental programs. Because of the lack of biosynthetic and signaling mutants, the regulatory roles of cytokinins are not well understood. We genetically engineered cytokinin oxidase expression in transgenic tobacco plants to reduce their endogenous cytokinin content. Cytokinin-deficient plants developed stunted shoots with smaller apical meristems. The plastochrone was prolonged, and leaf cell production was only 3-4% that of wild type, indicating an absolute requirement of cytokinins for leaf growth. In contrast, root meristems of transgenic plants were enlarged and gave rise to faster growing and more branched roots. These results suggest that cytokinins are an important regulatory factor of plant meristem activity and morphogenesis, with opposing roles in shoots and roots.

Cytokinins↗

PubMed2002

Prospective isolation of human clonogenic common myeloid progenitors.

The hierarchical development from hematopoietic stem cells to mature cells of the hematolymphoid system involves progressive loss of self-renewal capacity, proliferation ability, and lineage potentials. Here we show the prospective isolation of early developmental intermediates, the human clonogenic common myeloid progenitors and their downstream progeny, the granulocyte/macrophage and megakaryocyte/erythrocyte progenitors. All three populations reside in the lineage-negative (lin(-)) CD34(+)CD38(+) fraction of adult bone marrow as well as in cord blood. They are distinguishable by the expression of the IL-3R alpha chain, the receptor of an early-acting hematopoietic cytokine, and CD45RA, an isoform of a phosphotyrosine phosphatase involved in negative regulation of cytokine signaling. Multipotent progenitors, early lymphoid progenitors, and the here-defined myeloid progenitors express distinct profiles of hematopoiesis-affiliated genes. The isolation of highly purified hematopoietic intermediates provides tools to better understand developmental programs underlying normal and leukemic hematopoiesis.

Adult↗

PubMed2001

Local expression of expansin induces the entire process of leaf development and modifies leaf shape.

Expansins are a family of extracellular proteins proposed to play a key role in wall stress relaxation and, thus, in cell and tissue growth. To test the possible function of expansins in morphogenesis, we have developed a technique that allows transient local microinduction of gene expression in transgenic plants. We have used this system to manipulate expansin gene expression in various tissues. Our results indicate that local expansin expression within the meristem induces a developmental program that recapitulates the entire process of leaf formation. Moreover, local transient induction of expansin expression on the flank of developing primordia leads to the induction of ectopic lamina tissue and thus modulation of leaf shape. These data describe an approach for the local manipulation of gene expression and indicate a role for expansin in the control of both leaf initiation and shape. These results are consistent with the action of cell division-independent mechanisms in plant morphogenesis.

Gene Expression Regulation, Plant↗

PubMed2002

Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells.

The adult mouse intestine contains an intricate vascular network. The factors that control development of this network are poorly understood. Quantitative three-dimensional imaging studies revealed that a plexus of branched interconnected vessels developed in small intestinal villi during the period of postnatal development that coincides with assembly of a complex society of indigenous gut microorganisms (microbiota). To investigate the impact of this environmental transition on vascular development, we compared the capillary networks of germ-free mice with those of ex-germ-free animals colonized during or after completion of postnatal gut development. Adult germ-free mice had arrested capillary network formation. The developmental program can be restarted and completed within 10 days after colonization with a complete microbiota harvested from conventionally raised mice, or with Bacteroides thetaiotaomicron, a prominent inhabitant of the normal mouse/human gut. Paneth cells in the intestinal epithelium secrete antibacterial peptides that affect luminal microbial ecology. Comparisons of germ-free and B. thetaiotaomicron-colonized transgenic mice lacking Paneth cells established that microbial regulation of angiogenesis depends on this lineage. These findings reveal a previously unappreciated mechanism of postnatal animal development, where microbes colonizing a mucosal surface are assigned responsibility for regulating elaboration of the underlying microvasculature by signaling through a bacteria-sensing epithelial cell.

Animals↗

PubMed2001

Development of a two-part transcription probe to determine the completeness of temporal and spatial compartmentalization of gene expression during bacterial development.

We have developed a two-part test, using the Bacillus subtilis sacB/SacY transcription antitermination system, to evaluate the completeness of temporal and spatial compartmentalization of gene expression during bacterial cell development. Transcription of sacY(1-55) (encoding a constitutively active form of the antiterminator, SacY) is directed by one promoter, whereas transcription of sacB'-'lacZ (the target of SacY action) is directed by the same or another promoter. To obtain beta-galactosidase activity, SacY(1-55) needs to be present when sacB'-'lacZ is being transcribed. We tested the system by analyzing the spatial compartmentalization of the activities of RNA polymerase final sigma factors, which are tightly regulated during sporulation of B. subtilis: final sigma(F) and then final sigma(G) in the prespore, final sigma(E) and then final sigma(K) in the mother cell. We have confirmed that the activities of final sigma(F) and final sigma(E) are spatially compartmentalized. We have demonstrated that there is also sharp temporal compartmentalization, with little or no overlap in the activities of final sigma(F) and final sigma(G) or of final sigma(E) and final sigma(K). In contrast, we found no compartmentalization of the activity of the main vegetative factor, final sigma(A), which continued to be active alongside all of the sporulation-specific final sigma factors. We also found no temporal compartmentalization of expression of loci that are activated during the development of competent cells of B. subtilis, a developmental program distinct from spore formation. A possible mechanism to explain the temporal compartmentalization of final sigma(F) and final sigma(G) activities is that the anti-sigma factor SpoIIAB transfers from final sigma(G) to final sigma(F).

Bacillus subtilis↗

PubMed2003

Spx-dependent global transcriptional control is induced by thiol-specific oxidative stress in Bacillus subtilis.

The Spx protein of Bacillus subtilis represses activator-stimulated transcription by interacting with the C-terminal domain of RNA polymerase (RNAP) alpha subunit. Its concentration increases in cells lacking the ATP-dependent protease, ClpXP, resulting in severe effects on growth and developmental processes. Microarray analysis was undertaken to identify genes that are induced or repressed when Spx interacts with RNAP. The induced genes included those encoding products known to function in maintaining thiol homeostasis. Two genes, thioredoxin (trxA) and thioredoxin reductase (trxB), are transcriptionally induced under conditions of thiol-specific oxidative (disulfide) stress by a mechanism involving Spx-RNAP interaction. Disulfide stress also results in an increase in Spx-dependent transcriptional repression. The increase in Spx activity in cells encountering disulfide stress is due in part to a posttranscriptional mechanism of spx control resulting in an increase in Spx concentration. An spx null mutant and a strain bearing an allele of rpoA that prevents Spx-RNAP interaction show hypersensitivity to disulfide stress. From these results, it is proposed that Spx is an activator that mobilizes the operations necessary to reverse the effects of oxidative damage, but it also serves as a negative regulator that causes the postponement of developmental programs and energy-consuming growth-related functions while the cell copes with the period of stress.

Alleles↗

PubMed2000

Genetic analysis of calcium spiking responses in nodulation mutants of Medicago truncatula.

The symbiotic interaction between Medicago truncatula and Sinorhizobium meliloti results in the formation of nitrogen-fixing nodules on the roots of the host plant. The early stages of nodule formation are induced by bacteria via lipochitooligosaccharide signals known as Nod factors (NFs). These NFs are structurally specific for bacterium-host pairs and are sufficient to cause a range of early responses involved in the host developmental program. Early events in the signal transduction of NFs are not well defined. We have previously reported that Medicago sativa root hairs exposed to NF display sharp oscillations of cytoplasmic calcium ion concentration (calcium spiking). To assess the possible role of calcium spiking in the nodulation response, we analyzed M. truncatula mutants in five complementation groups. Each of the plant mutants is completely Nod- and is blocked at early stages of the symbiosis. We defined two genes, DMI1 and DMI2, required in common for early steps of infection and nodulation and for calcium spiking. Another mutant, altered in the DMI3 gene, has a similar mutant phenotype to dmi1 and dmi2 mutants but displays normal calcium spiking. The calcium behavior thus implies that the DMI3 gene acts either downstream of calcium spiking or downstream of a common branch point for the calcium response and the later nodulation responses. Two additional mutants, altered in the NSP and HCL genes, which show root hair branching in response to NF, are normal for calcium spiking. This system provides an opportunity to use genetics to study ligand-stimulated calcium spiking as a signal transduction event.

Calcium↗

PubMed1978

Growth state-dependent phenotypes of adult hepatocytes in primary monolayer culture.

A proliferation-competent adult rat liver cell monolayer system has been analyzed for tissue-specific functions during its growth cycle. High levels of the adult (L type) form of pyruvate kinase (EC 2.7.1.40) and glutathione S-transferase B ("ligand," EC 2.5.1.18) are observed during the early lag phase; they decline markedly during the logarithmic phase and reappear during the stationary phase. By contrast, elevated levels of the fetal (K type) form of pyruvate kinase and alpha1-fetoprotein production appear only after proliferation begins; this pattern diminishes slightly during stationary phase as the adult phenotype is restored. Albumin production continues throughout the entire growth cycle. These in vitro findings simulate those observed during hepatoproliferative transitions in the intact animal and, as such, constitute a developmental program for normal epithelial cells in primary culture.

Albumins↗

PubMed1979

Regulation of the tissue specificity of an enzyme by a cis-acting genetic element: evidence from interspecific Drosophila hybrids.

Homologous genes for alcohol dehydrogenase (alcohol:NAD+ oxidoreductase, EC 1.1.1.1) are expressed in qualitatively different patterns during the development of two closely related species of Hawaiian Drosophila. In interspecific hybrids, each parental structural allele is expressed according to the developmental program characteristic of the species from which it is derived. This provides strong evidence for a cis acting control element.

Alcohol Oxidoreductases↗

PubMed1980

A role for cyclic AMP in expression of developmentally regulated genes in Dictyostelium discoideum.

Starved cells of Dictyostelium discoideum begin to synthesize a new class of developmentally regulated proteins at about 13 hr of the 24-hr developmental program, concomitant with the formation of tips on the tight cell aggregates [Alton, T. H. & Lodish, H. F. (1977) Dev. Biol. 60, 180--206]. Continued synthesis of these proteins is normally dependent upon the integrity of the multicellular aggregates, because cells that have been disaggregated at 13 hr and shaken in suspension for 5 hr do not make these proteins. We show here that addition of 20 microM cyclic AMP to suspension cultures of disaggregated 13-hr cells caused synthesis of most of these late proteins to be maintained. Translation in an in vitro wheat germ system of total cellular RNA isolated from these cyclic AMP-stimulated suspension cells, or from normal aggregates, generated several proteins that were not encoded by the RNA isolated from equivalent suspension cells which had not been treated with cyclic AMP or from preaggregation cells. We conclude that cyclic AMP has a direct role in maintaining the synthesis of aggregation-dependent Dictyostelium proteins and in maintaining the level of the corresponding mRNAs.

Cell Aggregation↗

PubMed1981

Structural relationship and posttranslational modification of stage-specific proteins synthesized during early preimplantation development in the mouse.

The synthesis of stage-related proteins characteristic of meiotic maturation and early preimplantation development occurs in the absence of significant transcription. Previous work indicated that some of the stage-related proteins typical of the early postfertilization period are synthesized in unfertilized oocytes at the same time that they are detected in fertilized eggs. This observation has led to the suggestion that protein synthesis in newly fertilized eggs is regulated by an intrinsic developmental program initiated during the resumption of meiosis (meiotic maturation) and supported in part by previously untranslated mRNA. It also has been proposed that the rapid and complex changes in protein synthesis that characterize this period may involve differential gene expression or selective protein degradation, or both. To date, cell-free translation of oocyte RNA has not demonstrated the existence of a sizeable population of preformed mRNA that could support the observed changes in protein synthesis. I have tested the notion that the apparent changes in protein synthesis during early development in the mouse may be derived from families of proteins related both in amino acid sequence and posttranslational modification. The findings show that many changes in protein synthetic patterns related to early development after fertilization are independent of fertilization and involve the posttranslational modification of proteins with identical or very similar primary structures. The results are discussed with respect to current interpretations of quantitative and qualitative changes in protein synthesis during early mammalian development as they relate to differential gene expression and presumed activation of preformed mRNA.

Animals↗

PubMed1981

Repetitive DNA sequences cotranscribed with developmentally regulated Dictyostelium discoideum mRNAs.

We have isolated a clone of Dictyostelium discoideum genomic DNA, pB41-6, that contains sequences that are reiterated and interspersed in the genome. The expression of these reiterated sequences is developmentally regulated, and they appear to be linked only to developmentally regulated mRNAs. We have used clone pB41-6 to isolate a set of complementary cDNA clones. Analysis of two selected clones indicates that they encode developmentally regulated mRNA species and, by means of the repetitive elements they contain, hybridize to many developmentally regulated mRNAs. In addition, we have defined two families of mRNA species carrying these repetitive sequences: one is induced at 5.5 hr of development and the other is induced between 5.5 and 15 hr of development. Since most of the mRNA species that have sequences complementary to clone pB41-6 accumulate in a coordinated fashion during development, these sequences may play an important regulatory role in the developmental program of Dictyostelium.

Dictyostelium↗

PubMed1982

Hemoglobin switching in culture: evidence for a humoral factor that induces switching in adult and neonatal but not fetal erythroid cells.

An erythropoietic activity that exerts a profound effect on fetal Hb synthesis is present in fetal sheep sera and it attains a peak concentration at the end of the second to the middle of the third trimester of fetal life. The activity consistently inhibits the increased synthesis of fetal Hb in cultures of burst-forming units (BFUes) from normal adults. In cultures of BFUes from homozygous beta+-thalassemias the activity produces a striking decline in gamma chain synthesis, a decline in G gamma/A gamma chain synthesis ratio, and an increase in delta/gamma and alpha/non-alpha ratios--i.e., findings suggesting a genuine gamma-to-beta switch. The activity accelerates Hb F-to-Hb A switching in neonatal BFUe cultures but it has no effect on fetal Hb synthesis in cultures of BFUe obtained from human fetuses. These findings provide direct evidence that (a) humoral factors play a role in the regulation of the switch from fetal to adult Hb formation, and (b) progenitor cells from various stages of ontogeny respond differently to these factors. The results are compatible with the hypothesis that Hb switching during development is mediated through a change in a developmental program which controls the responsiveness of progenitor cells to "switching" activities in their environment.

Animals↗

PubMed1983

Keratin gene expression in mouse epidermis and cultured epidermal cells.

The major differentiation products of mouse epidermis are keratins of 40-70 kilodaltons (kDal). We have prepared a library of cDNA clones from total poly(A)+ RNA from newborn mouse epidermis. Clones corresponding to the major in vivo keratins of 55, 59, and 67 kDal have been isolated and characterized. By RNA blot analysis of poly(A)+ RNA from newborn mouse epidermis, we have identified RNA species that are approximately 1,600, 2,000, and 2,400 nucleotides in length and are complementary to the cDNAs for the 55-, 59-, and 67-kDal keratins, respectively. Analysis of RNA from primary cultures of newborn mouse epidermis by this same technique shows greatly reduced levels of these RNAs. Transcripts complementary to all three cloned cDNAs are abundant in 14- to 16-day embryonic and adult mouse skin. Thus, altered expression in culture does not appear to be due to induction of a developmentally programmed switch by placing the cells in culture but instead is due to factors modulating expression within the culture system. Because the 55-, 59-, and 67-kDal keratins are the major proteins in epidermis they probably represent keratin associated with terminal differentiation. The expression data suggest that cultured cells are blocked in expression of differentiation keratins but instead synthesize other keratin family members probably related to cytoskeletal functions.

Animals↗

PubMed1985

Developmental expression of nuclear genes that encode mitochondrial proteins: insect cytochromes c.

To investigate tissue-specific developmental regulation of mitochondrial biogenesis, we studied the expression of the Manduca sexta (tobacco hornworm moth) thoracic muscle cytochrome c gene during adult eclosion and used this information to obtain a cDNA clone for this gene, which in turn was used to isolate the corresponding Drosophila melanogaster gene. Over the 3 days prior to adult Manduca emergence, mitochondrial inner membranes become progressively more electron dense and lamellar, and, while there is no accumulation of apocytochrome c, the amount of the holoprotein increases 40-fold per insect thorax. As determined by in vitro translation and blot hybridization analysis, the major thoracic muscle cytochrome c gene is primarily regulated at the transcriptional level, with cytochrome c mRNA increasing from less than 0.01% to 0.04% of total poly(A)+ RNA and declining to an undetectable level by day 2 after eclosion. Furthermore, the ratio of cytochrome c to the other cytochromes remains the same at all times, indicating that these components of the respiratory chain follow coordinated developmental programs. By using polysome immunoadsorption, a poly(A)+ RNA population of greater than or equal to 95% cytochrome c mRNA was isolated from thoracic muscle tissue and was used to construct a cDNA library, which was screened by hybrid selection/translation. We report the sequence of one of those clones, pMSc750, and its use to isolate the major thoracic muscle cytochrome c gene of Drosophila.

Animals↗

PubMed1987

The lens protein alpha A-crystallin of the blind mole rat, Spalax ehrenbergi: evolutionary change and functional constraints.

The complete structure of the single-copy alpha A-crystallin gene of the blind mole rat (Spalax ehrenbergi) has been determined in order to elucidate the evolutionary effects of the loss of vision on a lens-specific protein and its gene. The alpha A-crystallin gene appears to have all the necessary transcriptional and translational signal sequences to be expressed in the rudimentary lens of the mole rat and gives rise to probably two protein products by means of alternative splicing, as in rodents with normal vision. Comparisons of the blind mole rat alpha A-crystallin sequence with alpha A sequences from other rodents reveal a considerable acceleration of the substitution rate at nonsynonymous positions in the mole rate lineage, which reflects a relaxation of selective constraints, but the acceleration is not to the extent that might be expected if the gene were now without any function. The remaining evolutionary constraints still imposed upon the mole rat alpha A-crystallin gene may possibly reflect the need for alpha-crystallin expression as an indispensable component in the developmental program of the atrophied eye.

Amino Acids↗

PubMed1987

Evolutionary changes in the developmental expression of silkmoth chorion genes and their morphological consequences.

Discrete changes in silkmoth choriogenesis have occurred during evolution, as exemplified in the present report in Antheraea polyphemus and Hyalophora cecropia. At the level of morphology, the chorion of A. polyphemus has surface structures, called aeropyle crowns, that are absent from H. cecropia. Aeropyle crowns form during the very late period of choriogenesis and consist of two substructures--lamellae and filler. Filler is present in H. cecropia in greatly reduced amounts. At the level of protein synthesis, overall similarities in the two species are maintained until the very late period of choriogenesis, when synthesis of aeropyle crown components is maximal. In H. cecropia, very late period-specific proteins are reduced in number and abundance. Several of these minor proteins are candidates for E1 and E2, the components of filler. E1 and E2 RNAs are about 35 times more abundant in A. polyphemus, despite very similar gene copy numbers and times of expression in the two species. These results support the hypothesis that evolutionary changes in chorion morphology have resulted from regulatory changes in the expression of chorion genes, either at the level of transcription or mRNA decay. The hypothesis that evolutionary changes in chorion morphology are based on terminal addition onto a preexisting developmental program is discussed.

Animals↗

PubMed1987

Developmental regulation of the estrogen receptor and the estrogen responsiveness of five yolk protein genes in the avian liver.

The magnitude of the expression of five yolk protein genes in the avian liver in response to exogenous estradiol is shown to be developmentally regulated. Though each of these yolk protein genes gains the capacity to respond to estradiol during embryonic development, we demonstrate that maximal responses for the different genes are achieved at distinct ages between 1 and 6 weeks after hatching. This observation prompted us to look for possible correlations between yolk protein gene expression and changes in the expression of estrogen receptors that might also occur after hatching. We discovered that indeed the maximal level of nuclear estrogen receptors (assayed following the administration of estradiol) increases progressively over this same period of development from approximately 1000 receptors per cell at 1 week after hatching to approximately 3500 receptors per cell at 6 weeks after hatching. The latter number represents the fully mature state, as comparable levels of receptors are present in the livers of egg-laying hens. Thus, though increases in the expression of estrogen receptors during embryonic liver development have previously been reported, our results indicate that the changes that occur after hatching are quantitatively far more significant to the developmental program for this transcription factor.

Age Factors↗