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PubMed1993

The cellular and molecular environment in leukemia.

Identification of normal viability-, growth-, and differentiation-inducing cytokines, the cells that produce them, and how cytokines interact in normal development, has made it possible to identify the cellular and molecular basis of normal development and changes in the developmental program that result in leukemia. When normal cells have been changed into leukemic cells, the malignant phenotype can again be suppressed in various ways. Results on the molecular control of growth, differentiation, and apoptosis in normal myeloid hematopoietic cells, changes in the normal developmental program in myeloid leukemia, and the suppression of malignancy in myeloid leukemia, have shown that (A) malignancy can be suppressed either with or without genetic changes in the tumor cells, (B) suppression of malignancy by inducing differentiation does not have to restore all the normal controls, and (C) genetic abnormalities which give rise to malignancy can be bypassed and their effects nullified by inducing differentiation and apoptosis which stop cells from multiplying.

Animals↗

PubMed1977

The area-code hypothesis: the immune system provides clues to understanding the genetic and molecular basis of cell recognition during development.

Numberous studies of embryogenesis have provided evidence for highly specific cell-surface recognition phenomena. These include both the interactions of neighboring cells and the specific cellular migrations which occur as the developmental program of the embryo progresses. The area-code hypothesis elaborate here is an attempt to provide a framework for understanding cell-recognition phenomena in development. This hypothesis is based on extensive genetic, molecular, and cellular studies of the immune system. These studies suggest that the following events occur during the differentiation of antibody-producing cells. 1) Somatic cell lines of antibody-producing cells undergo a modification of their DNA as they become committed to synthesize a particular type of antibody molecule. This chromosomal modification event is probably a DNA translocation which leads to a somatic rearrangement of certain antibody genes. 2) In each of the specific cell lineages the new arrangement of DNA is inherited by all subsequent generations of cells. 3) The developmental programs which control these genetic alterations may be employed in a programmed and reproducible fashion. This programming of antibody development is suggested because different embryos appear to become committed to the production of identical antibody molecules in the same developmental sequence. 4) Antibody molecules are initially displayed on the cell surface where they serve as highly specifici receptors to trigger the cell to proliferate and differentiate upon interacting with appropriate external molecular signals. 5) Antibody-producing cells display combinations of different molecules on their surfaces which cause each of a very large number of different cells to interact differently with their environment. 6) The genes which code for many of these cell-surface molecules are organized into multigene families. These observations as well as information from other developmental systems have led us to propose the area-code hypothesis. This hypothesis is concerned with the structure, function, and regulation of cell-surface molecules that mediate recognition phenomena during embryogenesis. Area-code molecules are cell-surface molecules which are involved in the specific recognition phenomena during growth and development. These molecules provide cells with distinct cell-surface addresses or phenotypes, and provide the basis for the specificity in cell-cell recognition during cell migrations and cell-cell interactions, as well as serving as receptors for diffusible differentiation signals. The area-code hypothesis has 3 main postulates. i) There is a progressive display of specific combinations of area-code molecules on the surfaces of cells during development. ii) The genetic programs which determine the specific expression of area-code molecules are in part controlled by DNA modifications. These chromosomal modifications are believed to channel cells into specific lineages uith progressively restricted developmental options...

Animals↗

PubMed1995

Experimental analysis of Msx-1 and Msx-2 gene expression during chick mandibular morphogenesis.

Homeobox-containing genes are thought to be involved in regulating pattern formation in a variety of tissues during embryogenesis. We have examined the expression of the homeobox-related genes Msx-1 and Msx-2 during the development of the chick mandibular arch. Northern blot hybridization indicates that transcripts for both Msx-1 (1.6 Kb) and Msx-2 (3 Kb) are present in the mandibular arch as early as stage 18. The levels of both transcripts in the whole mandible decrease as cartilage is formed in vivo and in vitro. Using in situ hybridization, transcripts of Msx-1 were localized in high amounts to the mesenchyme of the mesial tips of the arches. Msx-2 transcripts were localized in high amounts to medial regions of the arches. Little or no hybridization of either probe was detected in the chondrogenic and myogenic regions of the arches. Transcripts of both genes were also excluded from calcified bone and cartilage. Our results further demonstrate that the mesial tip mesenchyme expressing Msx-1 includes areas of highly proliferative cells and has in vitro chondrogenic potential. The region of mesenchymal cells expressing the Msx-2 gene overlap with areas of developmentally programmed cell death which also contain very few proliferative cells and lack chondrogenic potential in vitro. These results are consistent with the possibility that Msx-1 may be involved in the outgrowth of the mandibular arch and Msx-2 may be involved in both developmentally programmed cell death and delineating the non-chondrogenic region of the medial part of the mandibular arch.

Animals↗

PubMed1998

Spermiogenesis in Marsilea vestita: a temporal correlation between centrin expression and blepharoplast differentiation.

The motile male gamete of the water fern Marsilea vestita is a spirally shaped cell that possesses a complex cytoskeletal array of microtubules and approximately 140 cilia. Spermiogenesis in this organism is a rapid process that requires only approximately 11 h at 20 degrees C and involves the de novo synthesis of basal bodies from an organelle known as a blepharoplast. The developmental program that gives rise to the spermatozoids begins with nine mitotic divisions that occur in rapid succession during the first 5.5 h after imbibition of the dry microspore. During the next 5.5 h, the spermatids undergo a complicated differentiation process. We have asked what new proteins must be made for differentiation to proceed. Inhibitor treatments reveal that some translation is a necessary prerequisite for the differentiation and release of spermatozoids, but methionine-labeling studies demonstrate that relatively few types of proteins must be translated for this developmental program to reach completion. We have found that the dry microspores contain alpha-, beta-, and gamma-tubulin, at levels that may be sufficient for the entire developmental process. The abundance of the tubulins remains essentially constant until very late stages of spermiogenesis. In contrast to the tubulins, we show that centrin begins to increase in abundance at approximately 4 h after imbibition and that it reaches a peak at 6 h after imbibition. We also show that centrin mRNA is stored in the dry microspore, and that centrin protein abundance is regulated at the translational level. We believe that the translation of stored centrin transcripts serves as a rate-limiting step in the rapid differentiation process of spermiogenesis M. vestita. We suggest that centrin functions in the microtubule organizing centers that are required for the construction of the cytoskeleton and the motile apparatus in these structurally complicated cells.

Amanitins↗

PubMed1992

Evolution of alternate modes of development in ascidians.

Ascidians have evolved alternate modes of development in which the conventional tadpole larva is remodeled or eliminated. Adultation, the precocious development of adult features in the larval head, is caused by superimposing the larval and adult differentiation programs. Caudalization, the addition of muscle cells to the larval tail, is caused by enhancing muscle induction or increasing the number of muscle cell divisions before terminal differentiation. Adultation and caudalization are correlated with increased egg size, suggesting dependence on maternal processes. Anural development, the elimination of the larval stage, is caused by maternal and zygotic events resulting in abbreviation and deletion of larval developmental programs. An example of a maternal change in anural species is the modification of the egg cytoskeleton during oogenesis, whereas a zygotic change may involve altered cell interactions during embryogenesis. Interspecific hybridization experiments suggest that some aspects of anural development may be caused by loss-of-function mutations. The dissociation of developmental programs is a key process in changing the mode of development in ascidians.

Animals↗

PubMed1988

Developmentally regulated telomere addition in Tetrahymena thermophila.

To investigate the developmentally programmed telomere addition that accompanies chromosome fragmentation during macronuclear differentiation in Tetrahymena thermophila, five representative telomeric regions from the macronucleus were cloned and characterized in detail. The sequences adjacent to the telomeric (C4A2:T2G4) repeats on these five macronuclear ends had no significant sequence homology or shared secondary structure. Two developmentally independent examples of one macronuclear telomere had a 5 base pair difference in the position of the junction between the telomeric repeats and the adjacent sequences. A telomere-adjacent sequence, in the form of a synthetic oligonucleotide, was unable to prime the addition of telomeric repeats in vitro. The implications of these results for the mechanisms underlying developmentally programmed chromosome fragmentation and telomere addition in Tetrahymena are discussed.

Animals↗

PubMed1985

Bone matrix-directed chondrogenesis of muscle in vitro.

Bone matrix is the largely collagenous residue of demineralized bone. Experimental data demonstrate that a substance, which is acid-stable during demineralization, occurs as a part of bone matrix, and that it is capable of stimulating the redifferentiation of skeletal muscle into cartilage. Reproducibility of redifferentiation is high and all cells derived from embryonic mesoderm appear competent to yield cartilage. This effect is highly significant to the developmental biology of musculoskeletal tissues, as muscle and cartilage arise from a similar embryonic origin. With regard to the embryonic limb as a model system, it appears that both muscle and cartilage progenitor cells do not have rigidly-defined developmental programs, and that this is a result of their origin from a common pool of embryonic mesoderm. This pool originates as embryonic mesenchyme long before any evidence of limb development can be detected. It is proposed that the active component of bone matrix, termed "bone morphogenetic protein (BMP)," acts upon a tissue whose developmental program is not stabilized, or has been experimentally destabilized (by injury), to augment and sustain syntheses of cartilage extracellular matrix. The use of bone matrix, and active substances derived from it, suggests that differentiation is not irreversible. Hard tissue growth and repair may occur via recruitment of competent responding cells from a variety of nonchondrogenic sources, provided that the extracellular milieu (i.e., presence of BMP) is supportive.

Animals↗

PubMed1991

Overexpression of the cAMP receptor 1 in growing Dictyostelium cells.

cAR1, the cAMP receptor expressed normally during the early aggregation stage of the Dictyostelium developmental program, has been expressed during the growth stage, when only low amounts of endogenous receptors are present. Transformants expressing cAR1 have 7-40 times over growth stage and 3-5-fold over aggregation stage levels of endogenous receptors. The high amounts of cAR1 protein expressed constitutively throughout early development did not drastically disrupt the developmental program; the onset of aggregation was delayed by 1-3 h, and then subsequent stages proceeded normally. The affinity of the expressed cAR1 was similar to that of the endogenous receptors in aggregation stage cells when measured either in phosphate buffer (two affinity states with Kd's of approximately 30 and 300 nM) or in 3 M ammonium sulfate (one affinity state with a Kd of 2-3 nM). When expressed during growth, cAR1 did not appear to couple to its normal effectors since these cells failed to carry out chemotaxis or to elevate cGMP or cAMP levels when stimulated with cAMP. However, cAMP stimulated phosphorylation, and loss of ligand binding of cAR1 did occur. Like aggregation stage control cells, the cAR1 protein shifted in apparent molecular mass from 40 to 43 kDa and became highly phosphorylated when exposed to cAMP. In addition, the number of surface cAMP binding sites in cAR1 cells was reduced by over 80% during prolonged cAMP stimulation. These results define a useful system to express altered cAR1 proteins and examine their regulatory functions.

Cyclic AMP↗

PubMed2026

Maternal obesity in rats results in male-specific increases in genome-wide DNA methylation in postnatal offspring liver.

Male-specific peripubertal DNA demethylation in the liver has been reported in mice. Here, we investigated whether it also occurs in rats, the influence of maternal obesity and whether DNA demethylation changes contribute to observed sex-specific effects of maternal obesity in offspring. Female rats were fed a high-fat, high-sugar 'cafeteria' (Caf) diet before mating with standard chow-fed males. The offspring liver methylome and transcriptome were examined. Body weight was higher in Caf-fed dams prior to mating, during gestation and at parturition. Male and female offspring from Caf-fed dams had lower birth weights but higher adult weights and adiposity than offspring from chow-fed dams. A comparison of DNA methylation in 3-week-old weaner males versus female siblings from chow-fed dams did not reveal the male-specific DNA demethylation that was previously reported in mice. However, strong maternal diet effects in male weaner offspring methylation were observed. A comparison of female weaners from chow- versus Caf-fed dams showed a range of differences, with 39% of differentially methylated regions (DMRs) having higher methylation in Caf offspring and 61% of DMRs having higher methylation in chow offspring. In stark contrast, 99% of maternal-diet-induced DMRs in male weaner offspring had higher methylation in offspring from Caf-fed dams. This suggests that maternal obesity induces widespread hypermethylation in the male offspring liver at weaning. However, a comparison with RNA sequencing data revealed limited transcriptional changes at this developmental stage or in adult offspring. While these data highlight how environmentally sensitive DNA methylation is in the male rodent perinatal period, these methylation changes may not be a major contributor to sex differences in developmentally programmed liver disease.

Animals↗

PubMed1984

Programs advancing developmental psychopathology.

This report provides an overview of recent activities designed to further the integration of developmental perspectives in research involving infant and childhood psychopathology. Definitions are provided for what appears to be an emerging field of developmental psychopathology. Various methods to foster the growth of this interdisciplinary endeavor are presented. Examples given include: (a) informing key science administrators in funding institutions; (b) creating forums for research communication, evaluation and planning; (c) building researcher networks; (d) interpreting priorities at funding institutions; (e) providing new publication outlets; and (f) developing interdisciplinary research training programs.

Child↗

PubMed1981

A developmental treatment program for the chronic patient.

The need exists for a prescriptive treatment program for chronic mental patients within the state hospital. The community mental health center has not met the needs of the chronic patient, and the state hospital has developed neither the diagnostic nor treatment system to qualify as a viable aspect of the overall mental health delivery system. This article presents a diagnostic system based upon developmental stages which considers the whole person and allows prescriptive treatment for the chronic patient. The description of this treatment system within a state hospital suggests the role of the large institution in the total mental health delivery system.

Chronic Disease↗

PubMed2000

Intracellular signaling in the developing blastocyst as a consequence of the maternal-embryonic dialogue.

The success of blastocyst implantation is dependent on signaling between the embryo and the receptive endometrium. Intercellular signaling molecules, which include hormones, growth factors, and cytokines, have been identified that participate in the maternal-embryonic dialogue. These biologically active molecules may target uterine and/or embryonic tissues in a biochemical cascade that coordinates the two developmental programs during implantation. Two notable uterine products are calcitonin and heparin-binding epidermal growth factor-like growth factor, which are both expressed during the receptive phase of the endometrium in humans and in rodent models. We review data that demonstrate the ability of these molecules to accelerate blastocyst differentiation and delineate the respective intracellular signaling pathways that advance the embryonic developmental program. An understanding of the mediators regulating embryonic development in utero and their biochemical mechanisms of the action may provide insights for improvement of embryo culture in vitro prior to blastocyst transfer.

Animals↗

PubMed1994

Arabidopsis COP8, COP10, and COP11 genes are involved in repression of photomorphogenic development in darkness.

Wild-type Arabidopsis seedlings are capable of following two developmental programs: photomorphogenesis in the light and skotomorphogenesis in darkness. Screening of Arabidopsis mutants for constitutive photomorphogenic development in darkness resulted in the identification of three new loci designated COP8, COP10, and COP11. Detailed examination of the temporal morphological and cellular differentiation patterns of wild-type and mutant seedlings revealed that in darkness, seedlings homozygous for recessive mutations in COP8, COP10, and COP11 failed to suppress the photomorphogenic developmental pathway and were unable to initiate skotomorphogenesis. As a consequence, the mutant seedlings grown in the dark had short hypocotyls and open and expanded cotyledons, with characteristic photomorphogenic cellular differentiation patterns and elevated levels of light-inducible gene expression. In addition, plastids of dark-grown mutants were defective in etioplast differentiation. Similar to cop1 and cop9, and in contrast to det1 (deetiolated), these new mutants lacked dark-adaptive change of light-regulated gene expression and retained normal phytochrome control of seed germination. Epistatic analyses with the long hypocotyl hy1, hy2, hy3, hy4, and hy5 mutations suggested that these three loci, similar to COP1 and COP9, act downstream of both phytochromes and a blue light receptor, and probably HY5 as well. Further, cop8-1, cop10-1, and cop11-1 mutants accumulated higher levels of COP1, a feature similar to the cop9-1 mutant. These results suggested that COP8, COP10, and COP11, together with COP1, COP9, and DET1, function to suppress the photomorphogenic developmental program and to promote skotomorphogenesis in darkness. The identical phenotypes resulting from mutations in COP8, COP9, COP10, and COP11 imply that their encoded products function in close proximity, possibly with some of them as a complex, in the same signal transduction pathway.

Arabidopsis↗

PubMed2001

Distinct cytochrome P450 aromatase isoforms in zebrafish (Danio rerio) brain and ovary are differentially programmed and estrogen regulated during early development.

As a first step toward understanding estrogen's role in neurodevelopment, a PCR cloning strategy was used to isolate complementary DNAs encoding two distinct cytochrome P450 aromatase isoforms in adult zebrafish (Danio rerio) brain and ovary (termed P450aromB and P450aromA, respectively). Sequence and phylogenetic analysis showed that the zebrafish P450arom forms are orthologs of previously identified cyp19b and cyp19a genes in goldfish. On Northern blots, a single 4.4-kb transcript of the P450aromB subtype was identified in brain, and a 2.1-kb transcript of the P450aromA subtype in ovary, but RT-PCR showed a degree of overlapping expression. Both messenger RNA (mRNA) forms were detected in unfertilized eggs and 1.5 hpf (cleavage stage) embryos but declined by 12 hpf, indicating maternal transfer. A secondary rise in mRNAs between 12-24 hpf indicated the onset of embryonic cyp19b and -a transcription. Both mRNA species accumulated progressively to 120 hpf (early larval stage), but the relative magnitude and pattern of change was isoform specific. Estradiol (E(2,) 1 microM) advanced and amplified the developmentally programmed accumulation of P450aromB mRNA, and ICI164.384 decreased expressed levels, implying blockade of an endogenous estrogen mediated regulatory component. Conversely, E(2) had no effect or decreased P450aromA mRNA. The early embryonic expression of P450aromB and P450aromA isoforms, and differences in developmental programming and estrogen regulation, imply independent regulatory mechanisms and unique functions during major morphogenetic and differentiative events.

Aging↗

PubMed1988

Developmental characterization and chromosomal mapping of the 5-azacytidine-sensitive fluF locus of Aspergillus nidulans.

In Aspergillus nidulans, a fungus that possesses negligible, if any, levels of methylation in its genome, low concentrations of 5-azacytidine (5-AC) convert a high percentage of the cell population to fluffy phenotypic variants through a heritable modification of a single nuclear gene (M. Tamame, F. Antequera, J. R. Villanueva, and T. Santos, Mol. Cell. Biol. 3:2287-2297, 1983). This new 5-AC-altered locus, designated here fluF1, was mapped as the closest marker to the centromere that has been identified so far on the right arm of chromosome VIII. Of all mutagens tested, only 5-AC induced the fluffy phenotype with a significant frequency. Furthermore, we determined that the wild-type, dominant allele of the fluF gene was primarily accessible to modification by 5-AC at the initial stages of fungal vegetative growth. These results indicated that 5-AC does not act through random mutagenic action but, rather, that fluF constitutes a specific target for this drug during a well-defined period of fungal development. Alteration of fluF by 5-AC resulted in a dramatic modification of the developmental program of A. nidulans. The resulting fluffy clones were characterized by massive, uncontrolled proliferation of undifferentiated hyphae, a drastic delay in the onset of asexual differentiation (conidiation), and colonies with an invasive nature. These features are reminiscent of the malignant properties of tumor cells. We propose that the locus fluF plays a primary role in the control of cell proliferation in A. nidulans and that its alteration by 5-AC produces pleiotropic modifications of the developmental program of this fungus.

Aspergillus nidulans↗

PubMed1999

Specification of hematopoietic and vascular development by the bHLH transcription factor SCL without direct DNA binding.

Transcription factors, such as those of the basic-helix-loop-helix (bHLH) and homeodomain classes, are primary regulators of cell fate decisions and differentiation. It is considered axiomatic that they control their respective developmental programs via direct binding to cognate DNA sequences in critical targets genes. Here we test this widely held paradigm by in vivo functional assay of the leukemia oncoprotein SCL, a bHLH factor that resembles myogenic and neurogenic proteins and is essential for both hematopoietic and vascular development in vertebrates. Contrary to all expectation, we find that SCL variants unable to bind DNA rescue hematopoiesis from gene-targeted SCL(-)(/)(-) embryonic stem cells and complement hematopoietic and vascular deficits in the zebrafish mutant cloche. Our findings establish DNA-binding-independent functions of SCL critical for transcriptional specification, and should encourage reassessment of presumed requirements for direct DNA binding by other transcription factors during initiation of developmental programs.

Animals↗

PubMed2002

Unseen forces: the influence of bacteria on animal development.

The diversity of developmental programs present in animal phyla first evolved within the world's oceans, an aquatic environment teeming with an abundance of microbial life. All stages in the life histories of these early animals became adapted to microorganisms bathing their tissues, and countless examples of animal-bacterial associations have arisen as a result. Thus far, it has been difficult for biologists to design ways of determining the extent to which these associations have influenced the biology of animals, including their developmental patterns. The following review focuses on an emerging field, the goal of which is to understand the influence of bacteria on animal developmental programs. This integrative area of research is undergoing a revolution that has resulted from advances in technology and the development of suitable animal-bacterial systems for the study of these complex associations. In this contribution, the current status of the field is reviewed and the emerging research horizons are examined.

Animals↗

PubMed1998

Treatment of non-obese diabetic (NOD)/Severe-combined immunodeficient mice (SCID) with flt3 ligand and interleukin-7 impairs the B-lineage commitment of repopulating cells after transplantation of human hematopoietic cells.

Until recently, the identification of cellular factors that govern the developmental program of human stem cells has been difficult due to the absence of repopulation assays that detect human stem cells. The transplantation of human bone marrow (BM) or cord blood (CB) into non-obese diabetic (NOD)/severe-combined immunodeficient (SCID) mice has enabled identification of primitive human cells capable of multilineage repopulation of NOD/SCID mice (termed the SCID-repopulating cell [SRC]). Here, we examined the effect of long-term in vivo treatment with various combinations of human cytokines on the developmental program of SRC. Detailed flow cytometric analysis of engrafted mice indicated that the vast majority of the human graft of untreated mice was comprised of B lymphocytes at various stages of development as well as myeloid and primitive cells; T cells were not reproducibly detected. Many studies, including murine in vitro and in vivo data and human in vitro experiments, have suggested that flt3 ligand (FL) and/or Interleukin-7 (IL-7) promotes T- and B-cell development. Unexpectedly, we found that treatment of engrafted mice with the FL/IL-7 combination did not induce human T- or B-cell development, but instead markedly reduced B-cell development with a concomitant shift in the lineage distribution towards the myeloid lineage. Effects on lineage distribution were similar in engrafted mice transplanted with highly purified cells indicating that the action of the cytokines was not via cotransplanted mature cells from CB or BM cells. These data show that the lineage development of the human graft in NOD/SCID mice can be modulated by administration of human cytokines providing a valuable tool to evaluate the in vivo action of human cytokines on human repopulating cells.

Animals↗