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PubMed2006

Prenatal testosterone excess programs reproductive and metabolic dysfunction in the female.

Findings discussed in this review stress the importance of normal estrogen and androgen signaling at appropriate developmental time points in maintaining normal phenotypic expression, reproductive and metabolic function and document how inappropriate steroid signaling, at inopportune times can have undesirable outcomes. For example, inappropriate testosterone exposure during fetal life alters the developmental trajectory of the female culminating in a suite of disorders, which include intrauterine growth-retardation and postnatal catch up growth, phenotypic masculinization, reproductive neuroendocrine and ovarian disruptions leading to progressive loss of cyclicity and metabolic disruptions manifested as hyperinsulinemia.

Animals↗
PubMed2002

Mutations in sfdA and sfdB suppress multiple developmental mutations in Aspergillus nidulans.

Conidiophore morphogenesis in Aspergillus nidulans occurs in response to developmental signals that result in the activation of brlA, a well-characterized gene that encodes a transcription factor that is central to asexual development. Loss-of-function mutations in flbD and other fluffy loci have previously been shown to result in delayed development and reduced expression of brlA. flbD message is detectable during both hyphal growth and conidiation, and its gene product is similar to the Myb family of transcription factors. To further understand the regulatory pathway to brlA activation and conidiation, we isolated suppressor mutations that rescued development in strains with a flbD null allele. We describe here two new loci, designated sfdA and sfdB for suppressors of flbD, that bypass the requirement of flbD for development. sfd mutant alleles were found to restore developmental timing and brlA expression to strains with flbD deletions. In addition, sfd mutations suppress the developmental defects in strains harboring loss-of-function mutations in fluG, flbA, flbB, flbC, and flbE. All alleles of sfdA and sfdB that we have isolated are recessive to their wild-type alleles in diploids. Strains with mutant sfd alleles in otherwise developmentally wild-type backgrounds have reduced growth phenotypes and develop conidiophores in submerged cultures.

Aspergillus nidulans↗
PubMed2004

Clonal mosaic analysis of EMPTY PERICARP2 reveals nonredundant functions of the duplicated HEAT SHOCK FACTOR BINDING PROTEINs during maize shoot development.

The paralogous maize proteins EMPTY PERICARP2 (EMP2) and HEAT SHOCK FACTOR BINDING PROTEIN2 (HSBP2) each contain a single recognizable motif: the coiled-coil domain. EMP2 and HSBP2 accumulate differentially during maize development and heat stress. Previous analyses revealed that EMP2 is required for regulation of heat shock protein (hsp) gene expression and also for embryo morphogenesis. Developmentally abnormal emp2 mutant embryos are aborted during early embryogenesis. To analyze EMP2 function during postembryonic stages, plants mosaic for sectors of emp2 mutant tissue were constructed. Clonal sectors of emp2 mutant tissue revealed multiple defects during maize vegetative shoot development, but these sector phenotypes are not correlated with aberrant hsp gene regulation. Furthermore, equivalent phenotypes are observed in emp2 sectored plants grown under heat stress and nonstress conditions. Thus, the function of EMP2 during regulation of the heat stress response can be separated from its role in plant development. The discovery of emp2 mutant phenotypes in postembryonic shoots reveals that the duplicate genes emp2 and hsbp2 encode nonredundant functions throughout maize development. Distinct developmental phenotypes correlated with the developmental timing, position, and tissue layer of emp2 mutant sectors, suggesting that EMP2 has evolved diverse developmental functions in the maize shoot.

Base Sequence↗
PubMed1987

Development of substance P-like immunoreactivity in Xenopus embryos.

The development of substance P-like immunoreactivity (SPLI) was studied in the Xenopus embryonic nervous system in order to determine in which neuronal populations and at what developmental times SPLI is expressed. Although Rohon-Beard neurons initially were thought to be the only substance P-immunoreactive cells in the embryonic frog spinal cord, we have demonstrated that several neuronal phenotypes are immunoreactive. The earliest evidence of SPLI was seen at stage 28 (Nieuwkoop and Faber, '67), at which time only some trigeminal ganglion cells, their axons in the ophthalmic nerve, and axons in the lateral tracts of the hindbrain showed SPLI. In the embryonic brain at stages 29/30, 37/38, and 42, SPLI was seen in the hypothalamus, trigeminal ganglion cells and their peripheral axons, the sensory roots of cranial nerve IX/X, and axons in the hindbrain lateral tracts. At premetamorphic stages, SPLI was found in several populations that are immunoreactive in adult amphibia. In the embryonic spinal cord, Rohon-Beard neurons were labeled consistently with reaction product; there was a rostrocaudal time gradient of immunoreactivity with increasing development. The Rohon-Beard neurons were not immunoreactive at developmental stages in which axonal outgrowth was beginning (stage 21), but were strongly immunoreactive at stages in which target cells had been contacted (stage 29). Several types of interneurons in the spinal cord (as classified by Roberts and Clarke, '82) showed SPLI during embryonic stages. At premetamorphic stages the Rohon-Beard neurons began to disappear and the immunoreactive interneurons were distributed similarly to those reported in the adult. Dorsal root ganglia differentiated during these stages, and at this time some of the neurons belonging to these ganglia exhibited substance P-like immunoreactivity.

Animals↗
PubMed2003

Gene expression signatures identify novel regulatory pathways during murine lung development: implications for lung tumorigenesis.

Oligonucleotide array based analysis was conducted to examine the temporal pattern of gene expression across the various stages of lung development to identify regulatory pathways at key developmental time points. Whole embryo total RNA or embryonic lung total RNA was harvested from A/J mice at seven developmental stages. To investigate changes in gene expression during lung development, four samples from each stage were examined using Affymetrix U74Av2 murine oligonucleotide microarrays. From the over 12,000 genes and ESTs represented on the array, 1346 genes and ESTs were identified as having a significant change in expression between at least one time point and the others (p<0.001, Kruskal-Wallis test). Within this group of approximately 1300 genes, four patterns of expression were seen: (1) upregulation during the embryonic period of development (up-down); (2) upregulation during the postnatal period of lung development (down-up) and (3) fluctuating expression, up initially, down for one or more time points, and then up again (up-down-up); and (4) vice versa (down-up-down). Expression patterns of genes previously reported to be involved in pulmonary development were also examined. Using the pathway visualisation tool, GenMapp, at least three regulatory pathways were found to contain clusters of differentially expressed genes: Wnt signalling, cell cycle, and apoptosis. Furthermore, we have shown that many of the genes involved in lung development are either known oncogenes or tumour suppressor genes altered in lung cancer, such as Cyr61, Rassf1a, and Dutt1/Robo1, or putative lung cancer genes. In addition, the genes identified pertinent to early development may also serve as candidate susceptibility genes for various inherited lung cancer disorders as well as for various heritable disorders of lung development. These results will contribute to our understanding of novel aspects of the regulatory machinery for embryonic lung development and of the genes involved in lung tumorigenesis.

Animals↗
PubMed2003

Sex variations in the disclosure to parents of same-sex attractions.

The decision whether to disclose same-sex attractions to parents was explored through in-depth interviews with 164 young women and men. Participants were more likely to disclose to mothers than fathers, usually around age 19 years and in a face-to-face encounter. Mothers were told before fathers, largely because mothers asked or because youth wanted to share their life with them; fathers were told by someone other than their child or by the youth because it was time. The reason participants did not disclose to mothers was because it was not the right developmental time; the reason they did not disclose to fathers was because they were not close to them. Sons, more than daughters, feared the negative reactions of parents, who generally reacted in the same manner--supportive or slightly negative. Relationships with parents since disclosure generally had not changed or had improved. Sex of parent mattered more than sex of child on most domains.

Adolescent↗
PubMed1982

Developmental disfluency and emerging grammar. II. Co-occurrence of disfluency with specified semantic-syntactic structures.

From a corpus of over 47,000 spontaneous utterances from four nonstuttering preschool children who were beginning to use syntax, 4,881 multiword, disfluent utterances were identified. Semantic-syntactic structures were identified among the disfluent multiword utterances and differences in frequency of structures were examined. There was variability in the developmental disfluency of the individual children, but each child's pattern of disfluency was systematic across time. Developmental disfluency shifted across structures systematically for each child and appeared to reflect a "practice effect" for those children beginning to learn syntax. The co-occurrence of disfluency with specific syntactic structures supported the premise that developmental disfluency was more strongly attached to the syntax of utterances than to the production of particular words.

Child Language↗
PubMed2001

Androgens and isolation from adult tutors differentially affect the development of songbird neurons critical to vocal plasticity.

Song learning in oscine birds occurs during a juvenile sensitive period. One idea is that this sensitive period is regulated by changes in the electrophysiological properties of neurons in the telencephalic song nucleus lateral magnocellular nucleus of the anterior neostriatum (LMAN), a structure critical for song development but not adult singing. A corollary of this idea is that manipulations affecting the pace and quality of song learning will concomitantly affect the development of LMAN's electrophysiological properties. Manipulations known to affect song development include treating juvenile male zebra finches with exogenous androgens, which results in abnormally truncated adult songs, and isolation of the juvenile from adult tutors and their songs, which extends the sensitive period for song learning. Previously, we showed that synaptic transmission in LMAN changes over normal song development and that these changes are accelerated or retarded, respectively, by androgen treatment and isolation from an adult tutor. The intrinsic properties of LMAN neurons afford another potential target for regulation by steroid hormones and experience of adult tutors. Indeed previous studies showed that the capacity for LMAN neurons to fire action potentials in bursts, due to a low-threshold calcium spike, and the width of single action potentials in LMAN, wane over development. Here we analyzed these and other intrinsic electrophysiological features of LMAN neurons over normal development, then tested whether either early androgen treatment or isolating juveniles from adult tutors affected the timing of these changes. The present study shows that androgen but not isolation treatment alters the developmental time at which LMAN neurons progress from the bursting to nonbursting phenotype. In addition, other intrinsic properties, including the half-height spike width and the magnitude of the spike afterhyperpolarization (AHP), were found to change markedly over development but only changes to the AHP were androgen sensitive. Interestingly of all of the synaptic and intrinsic electrophysiological properties in LMAN studied to date, only the half-height spike width continues to change in the late juvenile stages of song learning. Furthermore raising juveniles in isolation from an adult tutor transiently delays the maturation of this property. The present results underscore that beyond their effects on LMAN's synaptic properties, both androgens and adult tutor experience are potent and selective regulators of the intrinsic properties of LMAN neurons.

Action Potentials↗
PubMed2003

Identification of spatial and temporal cues that regulate postembryonic expression of axon maintenance factors in the C. elegans ventral nerve cord.

Patterns of gene expression are under precise spatial and temporal control. A particularly striking example is represented by several members of the zig gene family, which code for secreted immunoglobulin domain proteins required for maintaining ventral nerve cord organization in Caenorhabditis elegans. These genes are coordinately expressed in a single interneuron in the ventral nerve cord, known as PVT. Their expression is initiated at a precise postembryonic stage, long after PVT has been generated in mid-embryogenesis. We define spatial and temporal cues that are required for the precise regulation of zig gene expression. We find that two LIM homeobox genes, the Lhx3-class gene ceh-14 and the Lmx-class gene lim-6 are coordinately required for zig gene expression in PVT. Temporal control of zig gene expression is conferred by the heterochronic gene lin-14, a nuclear factor previously implicated in developmental timing in various contexts. Loss of the lim-6 and ceh-14 transcription factors and the developmental timer lin-14 cause not only a loss of zig gene expression but also lead to defects in the maintenance of ventral nerve cord architecture. Overriding the normal spatiotemporal control of zig gene expression through expression of one of the zig genes under control of heterologous promoters also causes axon patterning defects in the ventral nerve cord. Our findings illustrate the importance of spatial and temporal control of gene expression in the nervous system and, furthermore, implicate heterochronic genes in postmitotic neural patterning events.

Animals↗
PubMed1992

Endogenous epidermal growth factor regulates the timing and pattern of embryonic mouse molar tooth morphogenesis.

The tooth organ provides a model for discrete patterns of morphogenesis over short periods of developmental time. Studies were designed to test the hypothesis that endogenous epidermal growth factor (EGF) functions to regulate multiple cusp molar tooth morphogenesis during embryonic mouse development. The relative levels of endogenous EGF and EGF receptor (EGFR) transcripts were determined in both enamel organ epithelia and dental ectomesenchyme by reverse transcription-polymerase chain reaction (RT-PCR) assays. EGF and EGFR were localized by immunohistochemistry; both antigenic determinants were demonstrated on the same odontogenic cells in cultured tooth explants. To examine EGF-mediated signal transduction, cap stage mouse molar tooth organs (E16) were cultured in serumless, chemically-defined medium as either (i) controls, or supplemented with (ii) tryphostin (an EGF receptor kinase inhibitor), (iii) tyrphostin plus exogenous EGF, and (iv) exogenous EGF. Antisense oligodeoxynucleotide (ODN) strategy was used to investigate the functions of endogenous EGF employing (i) non-treated control, (ii) sense ODN control, (iii) antisense ODN, (iv) exogenous EGF, (v) sense ODN with exogenous EGF, and (vi) antisense ODN with exogenous EGF. Tyrphostin inhibited DNA synthesis and produced a significant decrease in the volume of the explants. These effects were recovered by addition of exogenous EGF. Antisense ODN inhibition resulted in abnormal cusp formations, decreased DNA synthesis, total DNA, RNA and protein content, and decreased stellate reticulum and tooth explant volumes. The decreased tooth size was not uniform, the most pronounced effect was in the stellate reticulum. This pattern of changes was not seen when antisense ODN treatment was supplemented with exogenous EGF. These results suggest that during cap stage of odontogenesis endogenous EGF acts to stimulate DNA synthesis, which increases the cell number of specific phenotypes within the enamel organ epithelia, and thereby regulates molar tooth morphogenesis.

Animals↗
PubMed2003

Mammalian housekeeping genes evolve more slowly than tissue-specific genes.

Do housekeeping genes, which are turned on most of the time in almost every tissue, evolve more slowly than genes that are turned on only at specific developmental times or tissues? Recent large-scale gene expression studies enable us to have a better definition of housekeeping genes and to address the above question in detail. In this study, we examined 1581 human-mouse orthologous gene pairs for their patterns of sequence evolution, contrasting housekeeping genes with tissue-specific genes. Our results show that, in comparison to tissue-specific genes, housekeeping genes on average evolve more slowly and are under stronger selective constraints as reflected by significantly smaller values of Ka/Ks. Besides stronger purifying selection, we explored several other factors that can possibly slow down nonsynonymous rates in housekeeping genes. Although mutational bias might slightly slow the nonsynonymous rates in housekeeping genes, it is unlikely to be the major cause of the rate difference between the two types of genes. The codon usage pattern of housekeeping genes does not seem to differ from that of tissue-specific genes. Moreover, contrary to the old textbook concept, we found that approximately 74% of the housekeeping genes in our study belong to multigene families, not significantly different from that of the tissue-specific genes ( approximately 70%). Therefore, the stronger selective constraints on housekeeping genes are not due to a lower degree of genetic redundancy.

Animals↗
PubMed2006

The sugar phosphotransferase system of Streptomyces coelicolor is regulated by the GntR-family regulator DasR and links N-acetylglucosamine metabolism to the control of development.

Members of the soil-dwelling, sporulating prokaryotic genus Streptomyces are indispensable for the recycling of the most abundant polysaccharides on earth (cellulose and chitin), and produce a wide range of antibiotics and industrial enzymes. How do these organisms sense the nutritional state of the environment, and what controls the signal for the switch to antibiotic production and morphological development? Here we show that high extracellular concentrations of N-acetylglucosamine, the monomer of chitin, prevent Streptomyces coelicolor progressing beyond the vegetative state, and that this effect is absent in a mutant defective of N-acetylglucosamine transport. We provide evidence that the signal is transmitted through the GntR-family regulator DasR, which controls the N-acetylglucosamine regulon, including the pts genes ptsH, ptsI and crr needed for uptake of N-acetylglucosamine. Deletion of dasR or the pts genes resulted in a bald phenotype. Binding of DasR to its target genes is abolished by glucosamine 6-phosphate, a central molecule in N-acetylglucosamine metabolism. Extracellular complementation experiments with many bld mutants showed that the dasR mutant is arrested at an early stage of the developmental programme, and does not fit in the previously described bld signalling cascade. Thus, for the first time we are able to directly link carbon (and nitrogen) metabolism to development, highlighting a novel type of metabolic regulator, which senses the nutritional state of the habitat, maintaining vegetative growth until changing circumstances trigger the switch to sporulation. Our work, and the model it suggests, provide new leads towards understanding how microorganisms time developmental commitment.

Acetylglucosamine↗
PubMed2004

Multichannel apparatus for parallel monitoring of light scattering in Dictyostelium discoideum cell suspensions.

Suspensions of Dictyostelium discoideum amoebae display free-running light scattering oscillations at the onset of development. We describe a device to monitor these oscillations in several samples in parallel. The apparatus consists of a thermostated cuvette holder where up to eight cuvettes containing cell suspension are inserted. Cells are aerated and kept in suspension via an airlift. Infrared light emitted from a five-diode array passes through the suspension and is detected by an array of five light detecting diodes. The resulting signal is digitized and recorded with a sampling rate of two measuring points/second. The parallel analysis approach allows determination of the effects of adding of agents or of variations in the external conditions in the same batch of amoebae at the same developmental time point. This represents an advantage over the conventional single cuvette approach, as oscillation characteristics themselves are developmentally regulated. Moreover, as the new experimental setup enables simultaneous analyses of up to eight samples, the behavior of wild-type and several mutant strains can be compared under identical experimental conditions.

Animals↗
PubMed1982

Neonatal hyperviscosity. II. Effect of partial plasma exchange transfusion.

To determine the effect of partial plasma exchange transfusion, 20 newborn infants with neonatal hyperviscosity were randomly assigned to observation or treatment with partial plasma exchange transfusion within the first eight hours after birth. They were studied for organ involvement by roentgenogram, blood count, coagulation studies, and neurologic behavior and were followed up using the Brazelton Neonatal Behavior Assessment scale at 8, 24, and 72 hours and 2 weeks of age; in addition, ten control infants without hyperviscosity of similar birth weights and gestational ages were also studied. Exchange transfusion improved blood viscosity but both hyperviscous groups showed a higher proportion of abnormal results than did the control subjects. Infants receiving exchange transfusions subsequently improved during the period from 8 hours to 2 to 3 weeks of age, until they were indistinguishable from the control subjects. Neurologic improvement in hyperviscous infants who had not received exchange transfusions were significantly slower during this period. At 8 months of age, abnormal neurologic and developmental findings were impressive in both groups; no significant differences in neurologic abnormalities were noted at that time. Developmental delays, tremors, spastic diplegia, and monoparesis were found in four of six untreated infants and five of ten infants who had received exchange transfusions. A fine tremor was present in one control child.

Blood Viscosity↗
PubMed2004

Temporal control of differentiation by the insulin receptor/tor pathway in Drosophila.

Multicellular organisms must integrate growth and differentiation precisely to pattern complex tissues. Despite great progress in understanding how different cell fates are induced, it is poorly understood how differentiation decisions are temporally regulated. In a screen for patterning mutants, we isolated alleles of tsc1, a component of the insulin receptor (InR) growth control pathway. We find that loss of tsc1 disrupts patterning due to a loss of temporal control of differentiation. tsc1 controls the timing of differentiation downstream or in parallel to the RAS/MAPK pathway. Examination of InR, PI3K, PTEN, Tor, Rheb, and S6 kinase mutants demonstrates that increased InR signaling leads to precocious differentiation while decreased signaling leads to delays in differentiation. Importantly, cell fates are unchanged, but tissue organization is lost upon loss of developmental timing controls. These data suggest that intricate developmental decisions are coordinated with nutritional status and tissue growth by the InR signaling pathway.

Animals↗
PubMed2001

The development of the black blow fly, Phormia regina (Meigen).

The black blow fly, Phormia regina (Meigen) is a primary species commonly utilized to indicate a postmortem interval, or more appropriately a "time since colonization". Due to the importance of this species as a secondary myiasis producer in livestock operations, and more recently as a time since death indicator in the field of forensic entomology, a considerable amount of data on its growth and development has been generated. However, the developmental time as reported by these studies varies greatly, and current more detailed data is needed for use in medicocriminal entomology. Hourly developmental data is presented under constant temperatures of 10, 15, 20, 25, 30, 35 and 40 degrees C, and cyclic temperatures of 10-15, 15-25, 25-35 and 35-45 degrees C. This study is in agreement with the results reported by Kamal [Comparative study of thirteen species of sarcosaprophagous Calliphoridae and Sarcophagidae (Diptera). I. Bionomics, Ann. Entomol. Soc. Am. 51 (1958) 261] and Melvin [Incubation period of eggs of certain musciod flies at different constant temperatures, Ann. Entomol. Soc. Am. 27 (1934) 406] only at temperatures of 25 degrees C and below. Bishopp [Flies which cause myiasis in man and animals: some aspects of the problem, J. Econ. Entomol. 8 (1915) 317] reported a shorter developmental duration for larval stages than what was produced with our laboratory rearings.

Animals↗
PubMed1976

Rib anomalies in myelodysplasia. An approach to embryologic inference.

An embryologic teratogenic mechanism is reconstructed by utilizing the distribution of anomalous ribs in children with lumbosacral myelomeningocele. This methodology may help to coalesce information from experimental models of teratogenesis and from descriptive human embryology. It provides an approach to deductive reasoning about human structural anomalies based on dynamic embryonic models of teratogenesis. Availability of a developmental time scale, based for example on the distribution of defective ribs, may be useful in the study of other teratogenic and developmental processes.

Abnormalities, Multiple↗
PubMed1997

Timing of mating, developmental asynchrony and the sex ratio in mice.

According to the developmental asynchrony hypothesis, changing the time of mating within the estrous cycle could alter the interval between completion of blastocyst development and uterine responsiveness for implantation. This may then lead to sex ratio skews in animals that exhibit sex-differential blastocyst development, because uterine stage may now benefit either slow (female) or fast (male) developing blastocysts. To test this hypothesis, the responses of two strains of mice to altered mating dynamics were compared. In a strain that exhibits higher male than female blastocyst developmental rates, sex ratios became significantly female-biased when mated late during the estrous cycle as opposed to early mating. However, timing of mating did not affect sex ratios in a strain with synchronous development of male and female preimplantation embryos. Hence, it is concluded that developmental asynchrony between male and female blastocysts on the one hand, and blastocysts and uterus on the other, are indeed responsible for the effect of timing of mating on litter sex ratios in mice.

Animals↗