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PubMed1997

Programming the Drosophila embryo.

A critical step in understanding the mechanisms of development is in defining the steps at the molecular, cellular, and organismal levels in the developmental program for a given organism-so that given the egg one can predict not only how the embryo will develop but also how that embryo evolved from its ancestors. Using methods employed by chemists and engineers in modeling hierarchical systems, I have integrated current theory and experiment into a calculational method that can model early Drosophila embryogenesis on a personal computer. This quantitative calculation tool is simple enough to be useful for experimentalists in designing experiments yet detailed enough for theoreticians to derive new insights on the evolution of developmental genetic networks. By integrating the strengths of theoretical and experimental methods into a single engineering model that can compute the cascade of genetic networks in a real organism, I provide a new calculational tool that can apply current theory to current experimental data to study the evolution of developmental programs.

Animals↗
PubMed1996

Prevalence of selected developmental disabilities in children 3-10 years of age: the Metropolitan Atlanta Developmental Disabilities Surveillance Program, 1991.

PROBLEM/CONDITION: Serious developmental disabilities affect approximately 2% of school-age children and are lifelong conditions that incur substantial financial and societal costs. REPORTING PERIOD: January 1991-December 1991. DESCRIPTION OF SYSTEM: The Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP) monitors the prevalence of four serious developmental disabilities--mental retardation, cerebral palsy, vision impairment, and hearing impairment--among children 3-10 years of age in the five-county metropolitan-Atlanta area. Children who have at least one of the four developmental disabilities are ascertained through annual review of records at schools, hospitals, and other sources. RESULTS AND INTERPRETATION: During 1991, rates for mental retardation varied by age, race, and sex; rates ranged from 5.2 per 1,000 children to 16.6 per 1,000 children. Regardless of the absolute rate of mental retardation in each of the age-, race-, and sex-specific categories, severe mental retardation (i.e., an intelligence quotient of <50) accounted for one third of all cases. The overall crude rate of cerebral palsy was 2.4 per 1,000 children; however, the rate was higher among black children (3.1 per 1,000 children) than among white children (2.0 per 1,000 children). The rate of moderate to severe hearing impairment was 1.1 per 1,000 children, and the rate of vision impairment was 0.8 per 1,000 children. Rates of hearing impairment were higher among black males than among children in the other race and sex groups, whereas rates for vision impairment varied only slightly between these groups. The rates of the developmental disabilities were not adjusted for possible confounding factors (e.g., maternal education, family income, and various medical conditions). Consequently, the variation in rates may reflect social or other characteristics unique to the study population. ACTIONS TAKEN: MADDSP data will be used to direct early childhood intervention efforts to reduce the prevalence of these four developmental disabilities. MADDSP data also are being used to measure progress toward the year 2000 national objectives for the prevention of serious mental retardation.

Cerebral Palsy↗
PubMed1981

Constitutive gene expression in myeloid leukemia and cell competence for induction of differentiation by the steroid dexamethasone.

Regulation of the cytoplasmic protein changes during myeloid cell differentiation has been analyzed with two-dimensional gel electrophoresis and differentiation-defective cell mutants. The cells studied include a clone of myeloid leukemia cells (clone 11) that can be induced to differentiate to macrophages by the protein inducer MGI and the steroid dexamethasone (Dex) and mutant clones that were inducible for differentiation to macrophages by MGI but not by Dex. The mutants were not defective in the specific binding of [3H]Dex to cytoplasmic receptors or in the transport and nuclear binding of the receptor--steroid complex. The protein patterns in the mutants showed both specific constitutive protein changes and nonresponding proteins. Twenty-one percent of the Dex-induced protein changes and 2% of the MGI-induced protein changes in clone 11 were constitutively expressed in the mutants. In addition, 28% of the proteins that responded to Dex in clone 11 did not respond to Dex in the mutants, whereas only 4% of the proteins that responded to MGI in clone 11 did not respond to MGI. The higher percentage of constitutive changes was thus associated with a larger defect in induction. The proteins with an abnormal response to Dex still showed a normal response to MGI, and the constitutive changes and nonresponding proteins were different for the two inducers. It is suggested that specific constitutive protein changes expressed by the mutants produced an asynchrony in the developmental program, resulting in a defective response to Dex and to MGI, and that this may apply to other inducers and developmental programs.

Cell Differentiation↗
PubMed1985

Granulocyte functions during maturation of human promyelocytic leukemia cells.

Human promyelocytic leukemia cells (HL-60) mature into functional granulocytes in response to in vitro treatment with several classes of chemical agents. Compounds that increase intracellular adenosine 3':5' -cyclic monophosphate induce a modified program of maturation in which the cells demonstrate functional properties characteristic of mature phagocytic cells while remaining morphologically immature. We compared the developmental programs initiated by two well-studied inducers, retinoic acid and dimethyl sulfoxide, with the programs initiated by two inducers known to raise intracellular adenosine 3':5' -cyclic monophosphate; N6, O2-dibutyryl adenosine 3':5' -cyclic monophosphate and the combination of prostaglandin E2 and theophylline. In response to the increase in intracellular adenosine 3':5' -cyclic monophosphate, the cells ceased proliferation, expressed chemotactic receptors and demonstrated stimulated enzyme release within 24 h. Chemotaxis, adherence, NBT reduction and superoxide production appeared by 72 h, although the cells remained unchanged morphologically. A similar developmental program was induced by dimethylsulfoxide, but appearance of the markers was delayed by 48 h. Expression of these markers was delayed and incomplete in response to retinoic acid.

Bucladesine↗
PubMed1990

Multivariate analyses of cognitive and cognitive style variables based on hemisphere specialization theory predictive of success in a college developmental studies program.

Right and left cerebral hemisphere and limbic scores derived from the Herrmann Brain Dominance Profile, Scholastic Aptitude Test Verbal and Mathematics scores, and High School Grade Point Average were correlated with grades in college developmental courses in reading, English, and mathematics for 146 students. Pearson correlations ranged from -.27 to .42. Multiple correlations with seven predictors ranged from .45 to .55, and from .14 to .37 for the profile scores alone. Discriminant analyses yielded hit-rates (predictive of classification of success and failure/actual classification) of 69%/72% in Reading, 76%/75% in English, and 66%/71% in Mathematics.

Achievement↗
PubMed1995

A school-based anger management program for developmentally and emotionally disabled high school students.

Using Novaco's cognitive-behavioral conceptualization of anger, several practitioners developed cognitive-behavioral approaches for effectively intervening with aggressive youth. However, little attention has been paid to using these approaches with young people whose cognitive, emotional, and behavioral limitations appear to preclude them from benefiting from these interventions. A group program at a special school has demonstrated that older adolescents and young adults with diagnoses such as pervasive developmental delay, mental retardation, and autism can benefit from such a model if it is modified to meet their special learning needs. Through the use of daily logs, group reinforcement, role playing, skill building and relaxation techniques, normalizing anger, and providing liaison to classrooms, multiply handicapped students were able to learn the physiology, triggers, and consequences of anger as well as to develop coping strategies for managing their anger, while reducing aggressive acting out. Most of these students will enter protective work and residential settings in the future, and possessing these skills will facilitate their successful placement and increase the likelihood that some will succeed in entering some aspect of the adult mainstream.

Adolescent↗
PubMed1986

Children at risk: perinatal events, developmental delays and the effects of a developmental stimulation program.

This paper reports the findings of two studies done between 1977 and 1981 in the Philippines. The first study examined the performance of 911 children, with histories of perinatal risk events, on a restandardized Philippine (Metro-Manila) version of the Denver Developmental Screening Test (DDST) which was developed in 1980. This study established that the children performed significantly below Philippine norms. A second study, cognizant of the findings of the first, introduced nursing interventions designed to address some needs of preterm infants and their mothers. Findings suggest that development stimulation can significantly improve the developmental status of preterm infants.

Child↗
PubMed1993

Sex determination gene TASSELSEED2 of maize encodes a short-chain alcohol dehydrogenase required for stage-specific floral organ abortion.

Maize produces separate unisexual flowers through programmed abortion of preformed organ primordia. In the male inflorescence (tassel), stamen primordia develop to sexual maturity, while gynoecia (pistil primordia) are aborted. In tasselseed2 (ts2) mutant plants, floral structures in the tassel adopt a female developmental program. Here we report the transposon tagging and cloning of the TS2 gene, which plays a late but pivotal role in determining the sexual fate of floral meristems. Shortly before abortion of the gynoecium, Ts2 mRNA is expressed subepidermally in that primordium. Phenotypic instability of the Activator (Ac)-induced allele ts2-m1 indicates that late restoration of TS2 action in somatic tissues, which is correlated with Ac excision, reactivates the male developmental program. The predicted amino acid sequence of the Ts2 protein shows significant similarity to short-chain alcohol dehydrogenases, particularly hydroxysteroid dehydrogenases.

Alcohol Dehydrogenase↗
PubMed1998

Glial differentiation does not require a neural ground state.

Glial cells differentiate from the neuroepithelium. In flies, gliogenesis depends on the expression of glial cell deficient/glial cell missing (glide/gcm). The phenotype of glide/gcm loss- and gain-of-function mutations suggested that gliogenesis occurs in cells that, by default, would differentiate into neurons. Here we show that glide/gcm is able to induce cells even from a distinct germ layer, the mesoderm, to activate the glial developmental program, which demonstrates that gliogenesis does not require a ground neural state. These findings challenge the common view on the establishment of cell diversity in the nervous system. Strikingly, ectopic glide/gcm overrides positional information by repressing the endogenous developmental program. These findings also indicate that glial differentiation tightly depends on glide/gcm transcriptional regulation. It is likely that glide/gcm homologs act similarly during vertebrate gliogenesis.

Animals↗
PubMed1985

Parasite regulation of host insect metamorphosis: a new form of regulation in pseudoparasitized larvae of Trichoplusia ni.

When eggs of Trichoplusia ni (lepidoptera) are stung by a parasitic wasp, Chelonus sp., the developing host larvae precociously initiate metamorphosis ten days later. Precocious initiation of metamorphosis occurs even in 'pseudoparasitized' stung hosts which contain no living parasites at the time of symptoms of host regulation by the parasite. In feeding, penultimate instar, pseudoparasitized hosts, the corpora allata activity, hemolymph juvenile hormone esterase activity, in vivo rates of juvenile hormone metabolism and changes in hemolymph protein composition all follow the pattern of the normal last instar. This and other evidence suggests the entire developmental pattern of the last larval instar is precociously expressed in penultimate instar, pseudoparasitized hosts. The cause of precocious expression of the developmental program leading to metamorphosis is a significant decrease in the critical size parameter that, in normal larvae, signals attainment of the last instar. The induction, in preultimate instar larvae, of the entire feeding stage developmental program leading to metamorphic commitment, using either biochemical, surgical or parasitic experimental probes, has not been previously reported. The results have important implications for the study of host-parasite endocrine interaction, of normal insect metamorphosis and even of human puberty.

Animals↗
PubMed1989

Positioning of gene products during Caulobacter cell differentiation.

Caulobacter crescentus has one of the simplest known developmental programs that exhibits both temporal and spatial organization. A hallmark of the Caulobacter cell cycle is that the progeny cells that result from each cell division differ from one another with respect to structure and developmental program. The process of establishing asymmetry prior to cell division requires that a number of gene products be targeted to a pole of the predivisional cell and consequently segregated to one of the two progeny. Several products involved in flagellar biogenesis and the chemotaxis machinery are segregated to the swarmer cell. Evidence suggests that the protein product of some fla and che genes is targeted to the incipient swarmer cell pole. In the case of other flagellar genes, it is the mRNA that is apparently segregated to the swarmer cell. Two heat shock proteins, DnaK and Lon are specifically segregated to the progeny stalked cell.

Bacterial Proteins↗
PubMed1987

Characterization of genes which are deactivated upon the onset of development in Dictyostelium discoideum.

We have identified and begun characterizations of the differential expression of 15 genes whose corresponding mRNA levels decrease during the preaggregative period of the developmental program of Dictyostelium discoideum. Upon the onset of development, the mRNAs decrease from 5- to 1000-fold over the first 8 hr. The rates of loss of each mRNA were similar to one another but distinct, and the decreases were dependent on progress through the developmental program. One exception to this dependency was observed, and the decrease in this mRNA was dependent on the absolute time after initiation of development instead of progress through development. With two exceptions, the decreases in mRNA levels were dependent on developmental conditions and were not seen when cells were shaken in starvation buffer. When the polysomal distributions of each species were examined, three classes were found: most showed no significant shifts off of polysomes upon initiation of development, two were characterized by a 20% shift to nonpolysomal RNA fractions upon development, and two gave a 40-50% shift. Collectively, these characterizations reveal differences in behavior which suggest that deactivation of genes upon initiation of development in Dictyostelium involves more than one regulatory pathway.

Cloning, Molecular↗
PubMed1998

SdeK is required for early fruiting body development in Myxococcus xanthus.

Myxococcus xanthus cells carrying the Omega4408 Tn5lac insertion at the sde locus show defects in fruiting body development and sporulation. Our analysis of sde expression patterns showed that this locus is induced early in the developmental program (0 to 2 h) and that expression increases approximately fivefold after 12 h of development. Further studies showed that expression of sde is induced as growing cells enter stationary phase, suggesting that activation of the sde locus is not limited to the developmental process. Because the peak levels of sde expression in both an sde+ and an sde mutant background were similar, we conclude that the sde locus is not autoregulated. Characterization of the sde locus by DNA sequence analysis indicated that the Omega4408 insertion occurred within the sdeK gene. Primer extension analyses localized the 5' end of sde transcript to a guanine nucleotide 307 bp upstream of the proposed start for the SdeK coding sequence. The DNA sequence in the -12 and -24 regions upstream of the sde transcriptional start site shows similarity to the sigma54 family of promoters. The results of complementation studies suggest that the defects in development and sporulation caused by the Omega4408 insertion are due to an inactivation of sdeK. The predicted amino acid sequence of SdeK was found to have similarity to the sequences of the histidine protein kinases of two-component regulatory systems. Based on our results, we propose that SdeK may be part of a signal transduction pathway required for the activation and propagation of the early developmental program.

Amino Acid Sequence↗
PubMed1985

A detailed developmental and structural study of the transcriptional effects of insertion of the Copia transposon into the white locus of Drosophila melanogaster.

The copia insertion responsible for the wa mutation is 3' to the white promotor and in the same transcriptional orientation as white. First, we have analyzed the effects of the wa copia insertion on levels of polyadenylated white transcripts and find large, developmentally programmed effects. Second, we have isolated and sequenced an LTR-excision event involving the copia insertion at wa. This represents the first documented case of an LTR-excision event in Drosophila. This single copia LTR has developmentally programmed effects on white transcript levels qualitatively similar to the intact copia element. Third, we have characterized the structures of white transcripts from wa. We find polyadenylated white transcripts apparently having 3' termini in or near the 3' LTR of the wa copia insertion, as has been reported in limited studies of wa transcription in adults by others. These earlier studies also revealed wa transcripts apparently corresponding to polyadenylated terminus formation in the 5' LTR of the copia transposon; however, our more detailed studies reveal that these transcripts probably have other origins and that little, if any, polyadenylated terminus formation for white transcripts occurs in the 5' LTR of the wa copia insertion. Moreover, we find no polyadenylated terminus formation for white transcripts occurring in the single LTR of the wa LTR-excision product. Fourth, we find that each of three mutant alleles at su(wa) produces elevated levels of several classes of RNAs apparently corresponding to transcriptional readthrough of the wa copia transposon. Elevated levels of one presumptive readthrough transcript were observed previously in one su(wa) mutant strain. Fifth, we have confirmed the existence of a transcript initiated in the 3' LTR of the wa copia insertion and find the levels of this transcript to be strongly influenced by developmental stage and genetic background. Lastly, we have analyzed white transcripts produced by the whd81b11 allele, which carries an insertion of copia in the opposite transcriptional orientation and in a different position than the wa copia insertion. In contrast to the wa copia insertion allele, the whd81b11 allele produces polyadenylated white transcript levels very similar to the w+ case at the stages examined. Moreover, the whd81b11 copia element apparently produced polyadenylated terminus formation in white transcripts and we observe no effect of the allelic state of su(wa) on apparent readthrough of this stop site.(ABSTRACT TRUNCATED AT 400 WORDS)

Alleles↗
PubMed1988

A chemoattractant receptor controls development in Dictyostelium discoideum.

During the early stages of its developmental program, Dictyostelium discoideum expresses cell surface cyclic adenosine monophosphate (cyclic AMP) receptors. It has been suggested that these receptors coordinate the aggregation of individual cells into a multicellular organism and regulate the expression of a large number of developmentally regulated genes. The complementary DNA (cDNA) for the cyclic AMP receptor has now been cloned from lambda gt-11 libraries by screening with specific antiserum. The 2-kilobase messenger RNA (mRNA) that encodes the receptor is undetectable in growing cells, rises to a maximum at 3 to 4 hours of development, and then declines. In vitro transcribed complementary RNA, when hybridized to cellular mRNA, specifically arrests in vitro translation of the receptor polypeptide. When the cDNA is expressed in Dictyostelium cells, the undifferentiated cells specifically bind cyclic AMP. Cell lines transformed with a vector that expresses complementary mRNA (antisense) do not express the cyclic AMP receptor protein. These cells fail to enter the aggregation stage of development during starvation, whereas control and wild-type cells aggregate and complete the developmental program within 24 hours. The phenotype of the antisense transformants suggests that the cyclic AMP receptor is essential for development. The deduced amino acid sequence of the receptor reveals a high percentage of hydrophobic residues grouped in seven domains, similar to the rhodopsins and other receptors believed to interact with G proteins. It shares amino acid sequence identity and is immunologically cross-reactive with bovine rhodopsin. A model is proposed in which the cyclic AMP receptor crosses the bilayer seven times with a serine-rich cytoplasmic carboxyl terminus, the proposed site of ligand-induced receptor phosphorylation.

Amino Acid Sequence↗
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↗