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PubMed1997

Paternal repression of the imprinted mouse Igf2r locus occurs during implantation and is stable in all tissues of the post-implantation mouse embryo.

The insulin-like growth factor type 2 receptor, also known as the cation independent mannose-6-phosphate receptor (Igf2r) is an imprinted gene, which is repressed on the paternally inherited allele in midgestation mouse embryos. We have used a LacZ reporter gene, targeted into the endogenous gene, to investigate the developmental timing, tissue specificity and stability of the repression of the paternal allele. The LacZ expression pattern in pre- and post-implantation embryos, confirmed that Igf2r shows monoallelic expression only after implantation. We show here, additionally, that Igf2r shows biallelic expression in all cells of the preimplantation embryo at E4.5, and, that monoallelic expression is clearly present in all tissues at E6.5, in the early post-implantation embryo. Imprinted expression is maintained in later embryonic development and no tissue was observed to escape imprinting up to E13.5 of development. Thus, for Igf2r, the onset of monoallelic expression occurs in all cells during the implantation period and paternal repression is maintained in all tissues of the late developing embryo.

Alleles↗
PubMed1984

Morphogenetic tissue interactions during posterior commitment in palleal buds of the polystyelid ascidian, Polyandrocarpa misakiensis.

The development of chimeric double-anterior and double-posterior buds in the polystyelid ascidian, Polyandrocarpa misakiensis, was studied. Bud pieces used were allowed to develop for various time periods before the fusion operation. One-day double-half buds developed into complete zooids with normal anteroposterior polarity. In these cases, the bud half whose site of origin on the parent was higher (more posterior) than the partner formed the posterior organ, the digestive tract, of a resultant zooid. Two-day double-posterior buds developed into biposterior zooids that had two digestive tracts, whereas 2-day double-anterior buds still underwent pattern regulation in the same manner as 1-day buds (23-24 degrees C). Bianterior zooids could only be induced from 3-day double-anterior buds, suggesting that the anterior determination occurs later than the posterior determination. Next, a 3-day posterior half was combined with a 1-day posterior half from a higher site. Though "high-level" tissue has a high potential for posterior differentiation, the 1-day bud half failed to form the digestive tract. This result suggests that the 3-day bud half has acquired the ability to inhibit the formation of additional posterior structures. The kinetics of posterior-forming activity of developing bud pieces was measured using a 12-hr bud piece of the highest level as a probe. The activity increased with increasing developmental time, and the increase was accompanied by posterior inhibition activity. Buds of different positional levels showed different time courses of these activities. The results of this study show that the posterior end is the dominant region of developing ascidian buds.

Animals↗
PubMed2004

MicroRNA-responsive 'sensor' transgenes uncover Hox-like and other developmentally regulated patterns of vertebrate microRNA expression.

MicroRNAs (miRNAs) are a class of short ( approximately 22-nt) noncoding RNA molecules that downregulate expression of their mRNA targets. Since their discovery as regulators of developmental timing in Caenorhabditis elegans, hundreds of miRNAs have been identified in both animals and plants. Here, we report a technique for visualizing detailed miRNA expression patterns in mouse embryos. We elucidate the tissue-specific expression of several miRNAs during embryogenesis, including two encoded by genes embedded in homeobox (Hox) clusters, miR-10a and miR-196a. These two miRNAs are expressed in patterns that are markedly reminiscent of those of Hox genes. Furthermore, miR-196a negatively regulates Hoxb8, indicating that its restricted expression pattern probably reflects a role in the patterning function of the Hox complex.

Animals↗
PubMed1995

The heterochronic gene lin-29 encodes a zinc finger protein that controls a terminal differentiation event in Caenorhabditis elegans.

A hierarchy of heterochronic genes, lin-4, lin-14, lin-28 and lin-29, temporally restricts terminal differentiation of Caenorhabditis elegans hypodermal seam cells to the final molt. This terminal differentiation event involves cell cycle exit, cell fusion and the differential regulation of genes expressed in the larval versus adult hypodermis. lin-29 is the most downstream gene in the developmental timing pathway and thus it is the most direct known regulator of these diverse processes. We show that lin-29 encodes a protein with five zinc fingers of the (Cys)2-(His)2 class and thus likely controls these processes by regulating transcription in a stage-specific manner. Consistent with this role, a lin-29 fusion protein binds in vitro to the 5' regulatory sequences necessary in vivo for expression of col-19, a collagen gene expressed in the adult hypodermis. lin-29 mRNA is detected in the first larval stage and increases in abundance through subsequent larval stages until the final molt, when lin-29 activity is required for terminal differentiation.

Amino Acid Sequence↗
PubMed1997

Mist1: a novel basic helix-loop-helix transcription factor exhibits a developmentally regulated expression pattern.

Basic helix-loop-helix (bHLH) proteins often belong to a family of transcription factors that bind to the DNA target sequence -CANNTG- (E-box) that is present in the promoter or enhancer regions of numerous developmentally regulated genes. In this study, we report the isolation and initial characterization of a novel bHLH factor, termed Mist1, that was identified by virtue of its ability to interact with E-box regulatory elements in a yeast "one-hybrid" screening procedure. Northern analysis revealed that Mist1 transcripts are expressed in several adult tissues, including stomach, liver, lung, and spleen but no expression is detected in the heart, brain, kidney, or testis. During mouse embryogenesis, Mist1 mRNA is first observed at E10.5 in the primitive gut and in the developing lung bud. Expression persists through E16.5 and remains restricted primarily to the epithelial lining. Mist1 also is detected in skeletal muscle tissues beginning at E12.5, persisting throughout all embryonic stages examined although in older embryos and in the adult expression becomes severely reduced. At later developmental times, Mist1 transcripts also are found in the pancreas, submandibular gland, and adult spleen. As predicted, the Mist1 protein is nuclear and binds efficiently to E-box sites as a homodimer. Mist1 also is capable of binding to E-box elements when complexed as a heterodimer with the widely expressed E-proteins, E12 and E47. Surprisingly, although Mist1 binds to E-boxes in vivo, the Mist1 protein lacks a functional transcription activation domain. These observations suggest that Mist1 may function as a unique regulator of gene expression in several different embryonic and postnatal cell lineages.

Amino Acid Sequence↗
PubMed2000

Differential developmental expression and cell type specificity of Dictyostelium catalases and their response to oxidative stress and UV-light.

Cells of Dictyostelium discoideum are highly resistant to DNA damaging agents such as UV-light, gamma-radiation and chemicals. The genes encoding nucleotide excision repair (NER) and base excision repair (BER) enzymes are rapidly upregulated in response to UV-irradiation and DNA-damaging chemicals, suggesting that this is at least partially responsible for the resistance of this organism to these agents. Although Dictyostelium is also unusually resistant to high concentrations of H(2)O(2), little is known about the response of this organism to oxidative stress. To determine if transcriptional upregulation is a common mechanism for responding to DNA-damaging agents, we have studied the Dictyostelium catalase and Cu/Zn superoxide dismutase antioxidant enzymes. We show that there are two catalase genes and that each is differentially regulated both temporally and spatially during multicellular development. The catA gene is expressed throughout growth and development and its corresponding enzyme is maintained at a steady level. In contrast, the catB gene encodes a larger protein and is only expressed during the final stages of morphogenesis. Cell type fractionation showed that the CatB enzyme is exclusively localized to the prespore cells and the CatA enzyme is found exclusively in the prestalk cells. Each enzyme has a different subcellular localization. The unique developmental timing and cell type distribution suggest that the role for catB in cell differentiation is to protect the dormant spores from oxidative damage. We found that exposure to H(2)O(2) does not result in the induction of the catalase, superoxide dismutase, NER or BER mRNAs. A mutant with greatly reduced levels of catA mRNA and enzyme has greatly increased sensitivity to H(2)O(2) but normal sensitivity to UV. These results indicate that the natural resistance to oxidative stress is not due to an ability to rapidly raise the level of antioxidant or DNA repair enzymes and that the response to UV-light is independent from the response to reactive oxygen compounds.

Amino Acid Sequence↗
PubMed2006

Dynamic regulation of Drosophila nuclear receptor activity in vivo.

Nuclear receptors are a large family of transcription factors that play major roles in development, metamorphosis, metabolism and disease. To determine how, where and when nuclear receptors are regulated by small chemical ligands and/or protein partners, we have used a 'ligand sensor' system to visualize spatial activity patterns for each of the 18 Drosophila nuclear receptors in live developing animals. Transgenic lines were established that express the ligand binding domain of each nuclear receptor fused to the DNA-binding domain of yeast GAL4. When combined with a GAL4-responsive reporter gene, the fusion proteins show tissue- and stage-specific patterns of activation. We show that these responses accurately reflect the presence of endogenous and exogenously added hormone, and that they can be modulated by nuclear receptor partner proteins. The amnioserosa, yolk, midgut and fat body, which play major roles in lipid storage, metabolism and developmental timing, were identified as frequent sites of nuclear receptor activity. We also see dynamic changes in activation that are indicative of sweeping changes in ligand and/or co-factor production. The screening of a small compound library using this system identified the angular psoralen angelicin and the insect growth regulator fenoxycarb as activators of the Ultraspiracle (USP) ligand-binding domain. These results demonstrate the utility of this system for the functional dissection of nuclear receptor pathways and for the development of new receptor agonists and antagonists that can be used to modulate metabolism and disease and to develop more effective means of insect control.

Animals↗
PubMed2001

An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans.

Two small temporal RNAs (stRNAs), lin-4 and let-7, control developmental timing in Caenorhabditis elegans. We find that these two regulatory RNAs are members of a large class of 21- to 24-nucleotide noncoding RNAs, called microRNAs (miRNAs). We report on 55 previously unknown miRNAs in C. elegans. The miRNAs have diverse expression patterns during development: a let-7 paralog is temporally coexpressed with let-7; miRNAs encoded in a single genomic cluster are coexpressed during embryogenesis; and still other miRNAs are expressed constitutively throughout development. Potential orthologs of several of these miRNA genes were identified in Drosophila and human genomes. The abundance of these tiny RNAs, their expression patterns, and their evolutionary conservation imply that, as a class, miRNAs have broad regulatory functions in animals.

Animals↗
PubMed1995

Sex differences in vulnerability to developmental spatial learning deficits induced by limited binge alcohol exposure in neonatal rats.

The two main objectives of this study were (1) to replicate previous findings that 6 days of binge-like exposure to alcohol during the neonatal brain growth spurt induces significant place learning deficits in juvenile rats and (2) to determine whether more limited (3-day) binge-like exposure during the neonatal period induces place learning deficits and whether the effects depend on the developmental timing of the exposure. Using artificial rearing methods and a split-litter experimental design, groups of male and female neonatal rats were given binge-like exposure to 4.5 g/kg/day of ethanol in milk formula either on Postnatal Days (PD) 4-6, PD 7-9, or PD 4-9, which yielded mean peak blood alcohol concentrations of 230-260 mg/dl. Controls included an artificially reared gastrostomy control group (GC) given an isocaloric milk formula diet on PD 4-9 and a suckle control group reared normally by lactating dams. Acquisition of place learning in the Morris spatial navigation task was trained for 6 consecutive days beginning on PD 26; a probe trial was given at the end of the sixth day. As expected, both males and females given alcohol on PD 4-9 had significant deficits in acquisition and probe trial performance relative to SC and GC groups. Males given the PD 7-9 exposure had significant place learning deficits which were as severe as with the full 6-day exposure. The PD 4-6 exposure in males produced only a nonsignificant trend toward slower acquisition. Females were not significantly affected by either 3-day exposure. The latter phase of the neonatal brain growth spurt appears to constitute a sex-specific period of enhanced vulnerability to alcohol-induced developmental spatial learning deficits.

Animals↗
PubMed2003

Sexual differentiation of germ cells in XX mouse gonads occurs in an anterior-to-posterior wave.

Differentiation of mouse embryonic germ cells as male or female is dependent on the somatic environment of the gonad rather than the sex chromosome constitution of the germ cell. However, little is known about the initiation of germ cell sexual differentiation. Here, we traced the initiation of germ cell sexual differentiation in XX gonads using the Stra8 gene, which we demonstrate is an early molecular marker of female germ cell development. Stra8 is upregulated in embryonic germ cells of XX gonads prior to meiotic entry and is not expressed in male embryonic germ cells. A developmental time course of Stra8 expression in germ cells of XX gonads has revealed an anterior-to-posterior wave of differentiation that lasts approximately 4 days, from embryonic days 12.5 to 16.5. Consistent with these results, we find that embryonic ovarian germ cells upregulate the meiotic gene Dmc1 and downregulate the Oct4 transcription factor in an anterior-to-posterior wave. In complementary experiments, we find that embryonic XX gonads upregulate certain gene markers of somatic female differentiation in an anterior-to-posterior pattern, while others display a center-to-pole pattern of regulation. Thus, sexual differentiation and meiotic entry of germ cells in embryonic XX gonads progress in an anterior-to-posterior pattern that may reflect local environmental cues that are present in the embryonic XX gonad.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Colonic expression of c-myb is initiated in utero and continues throughout adult life.

c-myb expression is an indicator of hemopoietic cell proliferation and its down-regulation occurs as an early event in cellular differentiation in vitro. We have previously demonstrated c-Myb protein expression in normal adult colon and tumor-derived colonic cell lines and have also shown that the proliferation of colon carcinoma cell lines is c-myb dependent. This study used the techniques of RNase protection and immunohistochemistry to define c-myb mRNA and protein expression in the normal adult mouse and mouse embryos, with special focus on the colon. These experiments revealed wide-spread c-myb mRNA expression in mouse embryos including nonhemopoietic tissues, and developmental time course studies revealed alterations in organ-specific c-myb mRNA expression. Immunohistochemical studies confirmed the embryonal expression of c-Myb in concordance with the mRNA data as well as c-Myb expression throughout the length of the adult mouse colonic crypt. In contrast, staining for the proliferating cell nuclear antigen was confined to the lower one third of the crypt. In addition, c-Myb staining extended beyond that of the proliferating cell nuclear antigen within the germinal centers of the spleen. These data suggest that c-myb: (a) has a role in the embryonic development of nonhemopoietic organs; (b) plays a specific role in the biology of the normal adult colonic crypt; and (c) expression is not inextricably linked to proliferation in vivo.

Animals↗
PubMed2006

Comprehensive microarray analysis of Hoxa11/Hoxd11 mutant kidney development.

The Hox11 paralogous genes play critical roles in kidney development. They are expressed in the early metanephric mesenchyme and are required for the induction of ureteric bud formation and its subsequent branching morphogenesis. They are also required for the normal nephrogenesis response of the metanephric mesenchyme to inductive signals from the ureteric bud. In this report, we use microarrays to perform a comprehensive gene expression analysis of the Hoxa11/Hoxd11 mutant kidney phenotype. We examined E11.5, E12.5, E13.5 and E16.5 developmental time points. A novel high throughput strategy for validation of microarray data is described, using additional biological replicates and an independent microarray platform. The results identified 13 genes with greater than 3-fold change in expression in early mutant kidneys, including Hoxa11s, GATA6, TGFbeta2, chemokine ligand 12, angiotensin receptor like 1, cytochrome P450, cadherin5, and Lymphocyte antigen 6 complex, Iroquois 3, EST A930038C07Rik, Meox2, Prkcn, and Slc40a1. Of interest, many of these genes, and others showing lower fold expression changes, have been connected to processes that make sense in terms of the mutant phenotype, including TGFbeta signaling, iron transport, protein kinase C function, growth arrest and GDNF regulation. These results identify the multiple molecular pathways downstream of Hox11 function in the developing kidney.

Animals↗
PubMed1992

The effect of a five-month delay on children's and adults' eyewitness memory.

Child witnesses must endure a delay of around six months between observing or being the victim of an alleged offence and being required to give evidence in a criminal court. While the legal profession seem to believe that young children's memories are particularly sensitive to the passage of time, developmental psychology can offer little relevant data to support or refute this presumption. In the present study, children aged six and nine years and adults witnessed a staged event and were subsequently interviewed in the days following the event and/or five months later. Results indicate that while all witnesses forgot information over this period, the younger children (six years) recalled slightly less information than the older children and the adults. The total amount of incorrect information recalled did not increase over the same period. Two different interviewing techniques were used--cued recall vs. 'enhanced' recall--the latter incorporating some aspects of the cognitive interview procedure. No differences were found relating to the interview techniques employed. The results underline the importance of recording initial interviews with child witnesses wherever possible.

Adult↗
PubMed1988

Regulation of the mid-blastula transition in amphibians.

The cleavage cycles during early amphibian development are synchronous, rapid, and biphasic. There is no transcription and no growth of the embryo, and the nuclear cycle is independent of the cytoplasmic cleavage cycle. All components necessary for development through the blastula stage are provided by maternal stores. At the twelfth cleavage division, a major transition occurs that involves initiation of transcription, an elongation of the cell cycle, an increase in cell movement, and asynchrony of cell division. It is probable that the major controlling factor in the regulation of all the aforementioned events is the cell cycle. During early cleavage stages, the cell cycle is both rapid (30-35 min) and synchronous. There is evidence that the cycling time may be controlled by the presence of several mitotic factors, such as MPF, CSF (cytostatic factor), and a titratable component that binds to nuclear membranes. The rapid rate of DNA synthesis may inhibit the formation of transcription complexes, resulting in the absence of detectable transcription before the MBT. Cellular movement may also be inhibited in the rapidly dividing cell. As the cell cycle elongates (possibly due to the functional loss or sequestration of one or more of the mitotic control factors), the G1 and G2 phases are incorporated into the cell cycle. Under conditions of slower rates of DNA replication and the presence of the G1 and G2 phases, the transcriptional machinery becomes functional. It is apparent that at the MBT, not all classes of transcripts are activated simultaneously in every cell, nor is their expression regulated by a common mechanism. Incorporation of the G1 and G2 phases in the cell cycle may also permit the synthesis and assembly of microtubules and cytoskeletal components necessary for the initiation of the cell movements characteristic of this stage of development. The role of the cell cycle in controlling events at the MBT is supported by evidence from studies in which perturbation of the cell cycle that results in its elongation or arrest produces subsequent initiation of events that occur normally at the MBT. The MBT therefore appears to be a window in the developmental time frame, during which a number of molecular and morphogenetic events occur independently of one another, but all are necessary for subsequent morphogenesis and cellular differentiation. It is a transition from the strict reliance on the maternal program to a dependence on the new transcription from the embryonic genetic program. It is probable that the major regulatory mechanism involved in the occurrence of this constellation of cellular events is the change in the cell cycle.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Disturbed oligodendrocyte development and recovery from hypomyelination in a c-myc transgenic mouse mutant.

The complexity of interactions underlying the elaboration of myelin has been extensively demonstrated. We provide evidence that signals promoting myelination are not confined to the normal developmental time window for myelination and persist well into adult life. The 2-50 mutant, described previously, carries a c-myc transgene regulated by a myelin basic protein promoter. This mutant is characterised by severe hypomyelination and abnormal oligodendrocytes in early life, followed by loss of the phenotype and normal longevity. We show that c-myc expression in early oligodendrocyte development results in a substantial reduction of cells of this lineage. However, apparent complete recovery, associated with loss of c-myc expression, axonal survival, and gradual myelin accumulation, is observed by 4 months of age. Thus, stimulation of myelination continues during adult life until normal myelin levels are established. We propose that this mutant may contribute to the characterisation of oligodendrocyte responses to myelinating signals.

Age Factors↗
PubMed1998

The TATA binding protein in the sea urchin embryo is maternally derived.

The cDNA encoding the TATA binding protein was isolated from 8- to 16-cell and morula-stage embryonic libraries of two distantly related species of sea urchin, Strongylocentrotus purpuratus and Lytechinus variegatus, respectively. The two proteins are 96% identical over both the N- and C-terminal domains, suggesting a conservation of transcriptional processes between the two species. The prevalence of SpTBP transcripts at several developmental time points was determined using the tracer excess titration method, and the corresponding number of TBP protein molecules was determined by quantitative Western blot analysis. Our results indicate that the amount of TBP mRNA and protein per embryo remains relatively constant throughout development. An initial large pool of TBP protein (>10(9)) molecules in the egg becomes diluted as a consequence of cell division and decreases to about 2 x 10(6) molecules per cell by the gastrula stage. We found by in situ RNA hybridization that the oocyte contains a large amount of TBP mRNA which is depleted late in oogenesis so that the eggs and early embryos have extremely low levels of TBP mRNA. We conclude that the oocyte manufactures nearly all of the TBP protein necessary for embryogenesis.

Animals↗
PubMed2002

Differential display identifies neuroendocrine-specific protein-A (NSP-A) and interferon-inducible protein 10 (IP-10) as ethanol-responsive genes in the fetal rat brain.

Fetal alcohol exposure is the most common nonhereditary cause of mental retardation in the western world. Rats prenatally treated with ethanol liquid diet exhibit extensive defects in the brain that accurately model those observed in humans. To analyze the ethanol effects on gene expression during brain development, we performed mRNA differential display and two-dimensional electrophoresis on gestational day (G) 13 and G 16 brain from rats treated with ethanol liquid diet. Using mRNA differential display followed by a variety of quantitative analyses, three genes were confirmed to be ethanol-responsive. Among them was Neuroendocrine-Specific Protein-A (NSP-A), which is known to be affected by thyroid hormone in the cortex at this developmental time. However, two additional genes known to be thyroid hormone-responsive were unaffected by ethanol, indicating that interference with thyroid hormone action may not be a predominant pathway by which alcohol induces damage in the fetal brain. The observation that interferon-inducible protein-10 (IP-10) is up-regulated in ethanol-treated fetal brain may indicate the presence of a disease process recruiting CD8+ T-cells capable of interfering with myelination. The result of two-dimensional (2D) electrophoresis and Western analyses demonstrated that few changes in the abundance of individual proteins or the phosphorylation of proteins at threonine and tyrosine were induced by prenatal ethanol exposure. A critical analysis of the approaches used in the present study may be important for future studies in this field.

Animals↗
PubMed1990

Gene expression during endochondral bone development: evidence for coordinate expression of transforming growth factor beta 1 and collagen type I.

Subcutaneous implantation of demineralized bone particles (DBP) into rats induces the formation of a bone ossicle by a tightly controlled sequence of chondro- and osteo-inductive events which are directly comparable to those which occur in normal endochondral bone development. Although the morphological and biochemical sequence associated with endochondral bone formation in this model has been well characterized, to date little information is available as to the gene regulation by which these events occur. To examine the expression of genes in this system, RNA was isolated from implants every 2 days over a time course spanning 3 to 19 days after implantation of DBP into rats. Cellular levels of mRNA transcripts of cell-growth-regulated and tissue-specific genes were examined by slot blot analysis and compared to the morphological changes occurring during formation of the ossicle. Analysis of the mRNA levels of histone H4 and c-myc, markers of proliferative activity, revealed several periods of actively proliferating cells, corresponding to 1) production of fibroprogenitor cells (day 3), 2) onset of bone formation (day 9), and 3) formation of bone marrow (day 19). The mRNA levels of collagen type II, a phenotypic marker of cartilage, peaked between days 7 and 9 post-implantation, corresponding to the appearance of chondrocytes in the implant, and rapidly declined on day 11 (to 5% of maximum value) when bone formation was observed. The peak mRNA levels of collagen type I, found in fibroblasts and osteoblasts, occurred first with the onset of bone formation (days 7-10) and again during formation of bone marrow (day 19). This study has demonstrated that the temporal patterns of mRNA expression of cartilage type II and bone type I collagens coincide with the morphological sequence in this model of endochondral bone formation. Further, the mRNA levels of transforming growth factor beta 1 (TGF beta) were compared to those of collagen types I and II; a direct temporal correlation of TGF beta mRNA levels with that of collagen type I was found throughout the developmental time course. This observation of a tightly coupled relationship between TGF beta and type I collagen mRNA levels is consistent with a functional role for TGF beta in extracellular matrix production during in vivo bone formation.

Animals↗