The molecular and cellular basis of preimplantation mouse development.
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Animals↗
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Cellular development of the human fetus and maternal poverty.
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Body Weight↗
Checkpoints: controls that ensure the order of cell cycle events.
The events of the cell cycle of most organisms are ordered into dependent pathways in which the initiation of late events is dependent on the completion of early events. In eukaryotes, for example, mitosis is dependent on the completion of DNA synthesis. Some dependencies can be relieved by mutation (mitosis may then occur before completion of DNA synthesis), suggesting that the dependency is due to a control mechanism and not an intrinsic feature of the events themselves. Control mechanisms enforcing dependency in the cell cycle are here called checkpoints. Elimination of checkpoints may result in cell death, infidelity in the distribution of chromosomes or other organelles, or increased susceptibility to environmental perturbations such as DNA damaging agents. It appears that some checkpoints are eliminated during the early embryonic development of some organisms; this fact may pose special problems for the fidelity of embryonic cell division.
Animals↗
Formation of retinal ganglion cell topography during prenatal development.
A fundamental feature of the mammalian visual system is the nonuniform distribution of ganglion cells across the retinal surface. To understand the ontogenetic processes leading to the formation of retinal ganglion cell topography, changes in the regional density of these neurons were studied in relation to ganglion cell loss and the pattern of retinal growth in the fetal cat. Midway through the gestation period, the density of these neurons was only two to three times greater in the area centralis than in the peripheral retina, whereas shortly before birth this central-to-peripheral difference was nearly 20-fold. Age-related changes in the ganglion cell distribution were found not to correspond in time or magnitude to the massive loss of ganglion cells that occurs during prenatal development. Rather, the formation of ganglion cell density gradients can be accounted for by unequal expansion of the growing fetal retina-peripheral regions expand more than the central region, thereby diluting the peripheral density of ganglion cells to a greater degree. Nonuniform growth, in conjunction with differential periods of neurogenesis of the different types of retinal cells, appears to be a dominant factor regulating overall retinal topography. These results suggest that the differential regional expansion of the fetal retina underlies the formation of magnification factors in the developing visual system.
Animals↗
Rubella virus replication and links to teratogenicity.
Rubella virus (RV) is the causative agent of the disease known more popularly as German measles. Rubella is predominantly a childhood disease and is endemic throughout the world. Natural infections of rubella occur only in humans and are generally mild. Complications of rubella infection, most commonly polyarthralgia in adult women, do exist; occasionally more serious sequelae occur. However, the primary public health concern of RV infection is its teratogenicity. RV infection of women during the first trimester of pregnancy can induce a spectrum of congenital defects in the newborn, known as congenital rubella syndrome (CRS). The development of vaccines and implementation of vaccination strategies have substantially reduced the incidence of disease and in turn of CRS in developed countries. The pathway whereby RV infection leads to teratogenesis has not been elucidated, but the cytopathology in infected fetal tissues suggests necrosis and/or apoptosis as well as inhibition of cell division of critical precursor cells involved in organogenesis. In cell culture, a number of unusual features of RV replication have been observed, including mitochondrial abnormalities, and disruption of the cytoskeleton; these manifestations are most probably linked and play some role in RV teratogenesis. Further understanding of the mechanism of RV teratogenesis will be brought about by the investigation of RV replication and virus-host interactions.
Adult↗
Cyclic mechanical stretch inhibits cell proliferation and induces apoptosis in fetal rat lung fibroblasts.
Development of the pulmonary air sacs is crucial for extrauterine survival. Late fetal lung development is characterized by a thinning of the mesenchyme, which brings pneumocytes and endothelial cells into apposition. We hypothesized that mechanical stretch, simulating fetal breathing movements, plays an important role in this remodeling process. Using a Flexercell Strain Unit, we analyzed the effects of intermittent stretch on cell proliferation and apoptosis activation in fibroblasts isolated from fetal rat lungs during late development. On day 19, intermittent stretch increased cells in G(0)/G(1) by 22% (P = 0.001) and decreased in S phase by 50% (P = 0.003) compared with unstretched controls. Cell proliferation analyzed by 5-bromo-2'-deoxyuridine incorporation showed a similar magnitude of cell cycle arrest (P = 0.04). At this same gestational age, stretch induced apoptosis by two- to threefold over controls, assayed by DNA flow cytometry, terminal deoxynucleotidyl transferase-mediated dUTP-FITC nick-end labeling, and caspase-3 activation. These results indicate that mechanical stretch of fibroblasts isolated during the canalicular stage inhibits cell cycle progression and activates apoptosis. These findings are cotemporal with the mesenchymal thinning that normally occurs in situ.
Animals↗
Aberrant Myc expression in the murine trisomy 15 syndrome is correlated with prolonged proliferation in spongiotrophoblast cells of the placenta.
In the mouse the protooncogene Myc is localized to Chromosome 15. Embryos with trisomy 15 (Ts15) are severely retarded and die in utero at an early stage. The placenta of these embryos shows enlargement of the fetal spongiotrophoblast. In the spongiotrophoblast and giant cells of the normal euploid placenta, Myc expression declines from day 10.5 of gestation onward whereas Myc expression persists at a high level in Ts15 cells. At the same time these Ts15 cells show prolonged proliferation which consequently leads to the observed enlargement of that tissue layer in Ts15 placentas.
Animals↗
Stereology of the myocardium in embryos, fetuses and neonates of the rat.
We studied with quantitative methods the myocardium of 32 specimens of rats divided into three age groups: embryos, fetuses and neonates. Days of gestation were counted from the day following an overnight mating that was considered day 1 of gestation and only one animal per litter was used. The hearts were fixed in Bouin's fixative, sectioned and stained by routine methods. Stereological determinations were made on ventricular myocardium: (1) volume density of the myocytes [Vv(myocyte)] and interstitium [Vv(interstitium)], and (2) numerical density of the myocytes [Nv(myocyte) 1/mm3] calculated from fifteen optical dissector pairs per specimen. The total number of cardiac myocytes [N(myocyte)] was calculated as the product of Nv(myocyte) and the cardiac volume. The Nv(myocyte) increased from embryos to neonates, differences between embryos and fetuses and between embryos and neonates were statistically significant. The Vv(myocyte) increased from embryos to neonates (from 80.0 to 94.0%). During this period the Vv(interstitium) decreased from 21.0 to 5.5%. Differences of the Vv(myocyte) and Vv(interstitium) were significant comparing embryos with neonates and comparing fetuses with neonates. The N(myocyte) is roughly (mean +/- standard error of the mean) 9,297 +/- 487 in fetuses and 38,438 +/- 612 in neonates. This represents an increase of about 3.1 times from fetuses to neonates while the cardiac weight increased about 2.2 times in the same period. Coefficients of error for the Nv(myocyte) estimates averaged about 7.3%, for the Vv(myocyte) estimates averaged about 1.8%, and for the Vv(interstitium) estimates averaged about 9.1%. These results suggest a high mitotic activity in the rat myocardium during prenatal life and after birth.
Animals↗
Leydig cells and prostatic proliferation and secretion in the foetus and neonate in normal and complicated pregnancy.
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Cell Count↗
Ultrastructure of developing and malignant germ cells.
Ultrastructural studies have provided special insights on the growth and differentiation of normal and neoplastic germ cells. Prespermatogenic germ cells in the fetal and postnatal testis are large spherical to ovoid cells characterized by a central symmetrical nucleus, prominent reticular nucleoli and abundant cytoplasm with accumulation of glycogen and paucity of other organelles. Similar findings have been observed in seminoma and intratubular neoplasia. These observations support origin of the tumours from germ cells at early stages of differentiation. Evidence is presented to suggest that the pathogenesis of germ cell neoplasia involves excessive proliferation of precursor germ cells associated with loss of intercellular communication.
Cell Differentiation↗
Altered immune function in human newborns after prenatal administration of betamethasone: enhanced natural killer cell activity and decreased T cell proliferation in cord blood.
During the course of human pregnancy, glucocorticoid (GC) treatment is given when preterm delivery is expected. This treatment is successful in stimulating the development of the fetal lung. However, in animal studies, a number of side effects of perinatal GC treatment have been described. The aim of the present study was to evaluate in humans the effects of antenatal GC treatment on development of the immune system. In addition, we examined the development of immune reactivity in infants born preterm and at term who did not receive GC treatment antenatally. We tested mitogen-induced T cell proliferation, natural killer cell activity, and lipopolysaccharide-induced IL-6 production in cord blood samples. We found that there is a significant effect of gestational age on the capacity of T cells to proliferate and of natural killer cells to kill K562 tumor cells. The capacity to produce IL-6 does not change between gestational age 26 and 41 wk. Moreover, our results show that antenatal treatment with GC does have immunomodulatory effects: T cell proliferation is decreased in infants born very preterm (gestational age 26-31 wk) as well as in infants born between 32 and 36 wk of gestation. In contrast, the activity of natural killer cells is only increased in GC-treated infants born between 26 and 31 wk. We did not observe a significant effect of antenatal GC treatment on the capacity to produce IL-6.
Betamethasone↗
Proliferation and apoptosis in the human adrenal cortex during the fetal and perinatal periods: implications for growth and remodeling.
After 10-15 weeks of gestation, the human fetal adrenal cortex undergoes rapid growth due to enlargement of a specialized cortical compartment known as the fetal zone (FZ). Soon after birth, the FZ regresses and the adult zonation pattern develops at least in part from cells derived from the persistent definitive zone (DZ), a thin layer of tightly packed cells surrounding the FZ. We postulated that growth of the fetal adrenal cortex involves zone-specific cellular hyperplasia, whereas the postnatal involution of the FZ is due to apoptosis. Therefore, we investigated the pattern of cellular proliferation and death in the FZ and DZ of the human fetal and postnatal adrenal cortex using immunohistochemical staining for proliferating cell nuclear antigen as a marker of mitosis and in situ detection of DNA fragmentation as a marker of apoptosis. Between 10-14 weeks' gestation, the mitotic indexes (percentage of proliferating cell nuclear antigen-positive cells) in the DZ (26.46 +/- 2.95%) and in the FZ (21.26 +/- 2.57%) were not significantly different. Between 15-20 weeks gestation, the mitotic index increased significantly (P < 0.05) in both zones (FZ, 33.84 +/- 5.21%; DZ, 67.45 +/- 7.58%) relative to levels before 15 weeks. This increase persisted between 21-24 weeks gestation (FZ, 39.5 +/- 4.22%; DZ, 58.63 +/- 6.83%). Interestingly, after 14 weeks, the mitotic index of the DZ was significantly greater (P < 0.05) than that of the FZ. In adrenal specimens obtained from infants born prematurely and treated in utero with glucocorticoid, the mitotic indexes in the FZ and DZ were significantly decreased. At all stages of gestation, no apoptotic nuclei were detected in the DZ. However, scattered apoptotic nuclei were detected in the central portions of the FZ. The number of apoptotic nuclei in the inner FZ increased with advancing gestation and was maximal during the first postnatal month. To identify factors that may regulate apoptosis, primary cultures of midgestation FZ cells were treated with activin A and transforming growth factor-beta (TGFbeta). Activin A and TGFbeta both induced apoptotic cell death, as assessed by internucleosomal DNA cleavage (DNA laddering). Induction of apoptosis by activin A was prevented by concomitant addition of follistatin, an activin-binding protein. Taken together, these data indicate that 1) growth of the human fetal adrenal cortex involves cellular hyperplasia, mainly in the DZ and to a lesser extent in the FZ, which is probably dependent on ACTH; and 2) apoptosis occurs predominantly in the inner cortical compartment and may be responsible for the rapid regression of the FZ after birth, a process that may be regulated by activin A and/or TGFbeta.
Activins↗
Persistent and high levels of Hes1 expression regulate boundary formation in the developing central nervous system.
The developing central nervous system is partitioned into compartments by boundary cells, which have different properties than compartment cells, such as forming neuron-free zones, proliferating more slowly and acting as organizing centers. We now report that in mice the bHLH factor Hes1 is persistently expressed at high levels by boundary cells but at variable levels by non-boundary cells. Expression levels of Hes1 display an inverse correlation to those of the proneural bHLH factor Mash1, suggesting that downregulation of Hes1 leads to upregulation of Mash1 in non-boundary regions, whereas persistent and high Hes1 expression constitutively represses Mash1 in boundary regions. In agreement with this notion, in the absence of Hes1 and its related genes Hes3 and Hes5, proneural bHLH genes are ectopically expressed in boundaries, resulting in ectopic neurogenesis and disruption of the organizing centers. Conversely, persistent Hes1 expression in neural progenitors prepared from compartment regions blocks neurogenesis and reduces cell proliferation rates. These results indicate that the mode of Hes1 expression is different between boundary and non-boundary cells, and that persistent and high levels of Hes1 expression constitutively repress proneural bHLH gene expression and reduce cell proliferation rates, thereby forming boundaries that act as the organizing centers.
Animals↗
Multiple cell interactions are required for fate specification during male spicule development in Caenorhabditis elegans.
The B blast cell divides postembryonically in C. elegans males to produce 47 progeny that include all of the cells of the copulatory spicules. During the early development of the B lineage, the anterior daughter of B, B.a, generates eight cells. These cells migrate to form four pairs of cells that flank the developing cloaca (ventral, dorsal, and two identical lateral pairs). For each pair, the more anterior cell produces a distinct lineage ('anterior fate') from the posterior cell ('posterior fate'). For the ventral and dorsal pairs, either cell can migrate to the anterior position and produce the anterior lineage, and the other cell migrates posterior and produces the posterior lineage (Sulston and Horvitz, 1977, Dev. Biol. 56, 110-156). The migration is variable, although the resultant fate pattern is invariant. In the two lateral pairs, both the migration and fate pattern are invariant. Using a laser microbeam to selectively ablate neighboring cells we have found that the cells of the lateral pair also respond to positional cues. For all four pairs other male-specific blast cells provide extracellular cues. In general, F and U promote anterior fates, Y promotes some posterior fates, and the B.a progeny promote posterior fates. Several of these cues are redundant. By ablating combinations of cells we have deduced how these signals may act in concert to specify the fates of the B.a progeny. We propose that fate specification in these pairs depends on three general classes of extracellular cues: positional cues, modulators of positional cues, and lateral signals. The B lineage thus provides an opportunity to study with single cell resolution the integration of multiple intercellular signals.
Animals↗
Specification of anterior-posterior differences within the AB lineage in the C. elegans embryo: a polarising induction.
In a C. elegans embryo the third cleavages of descendants of the anterior blastomere AB of the 2-cell stage create pairs of blastomeres that develop differently. By laser ablation experiments we show that the fates of all the posterior daughters of this division depend on an induction occurring three cleavages before these blastomeres are born. The time of induction precludes a direct effect on cell fate. Alternatively, we suggest that the induction creates a heritable cell polarity which is propagated through several divisions. We suggest a model to demonstrate how a signal could be propagated through several rounds of cell division. An important implication of our observations is that this early induction acts to specify blastomere identity, not tissue type. A detailed lineage analysis revealed that altering the inductive signal alters complex lineage patterns as a whole. The induction described here, together with two inductions described previously can be used to illustrate how the anterior portion of the C. elegans embryo can be successively subdivided into blastomeres with unique developmental potential.
Animals↗
The Drosophila kinesin-like protein KLP3A is required for proper behavior of male and female pronuclei at fertilization.
Drosophila melanogaster females homozygous for mutations in the gene encoding the kinesin-like protein KLP3A are sterile (Williams et al., 1995). We have investigated the basis of this sterility. The eggs produced by KLP3A mutant mothers are fertilized by sperm, and female meiosis appears to occur normally. However, the large majority of these embryos arrest their development soon thereafter with a characteristic phenotype. The four nuclei produced by female meiosis associate together in a polar body-like structure, while a bipolar spindle is established around the metaphase-arrested male pronucleus. Thus, the major defect caused by depletion of the KLP3A protein is either in specification of the female pronucleus, or in migration of the male and female pronuclei toward each other. We have also found that the KLP3A protein is located throughout the metaphase spindle during meiosis and the early embryonic mitotic divisions, but later accumulates specifically at the midzone of these same spindles during telophase. The protein is also present on two other microtubule structures: the sperm aster; and the radial, monastral array of microtubules established between the two meiosis II spindles. We discuss these results in light of possible functions of the KLP3A protein in pronuclear specification and migration.
Anaphase↗
Unique functions of Sonic hedgehog signaling during external genitalia development.
Coordinated growth and differentiation of external genitalia generates a proximodistally elongated structure suitable for copulation and efficient fertilization. The differentiation of external genitalia incorporates a unique process, i.e. the formation of the urethral plate and the urethral tube. Despite significant progress in molecular embryology, few attempts have been made to elucidate the molecular developmental processes for external genitalia. The sonic hedgehog (Shh) gene and its signaling genes have been found to be dynamically expressed during murine external genitalia development. Functional analysis by organ culture revealed that Shh could regulate mesenchymally expressed genes, patched 1 (Ptch1), bone morphogenetic protein 4 (Bmp4), Hoxd13 and fibroblast growth factor 10 (Fgf10), in the anlage: the genital tubercle (GT). Activities of Shh for both GT outgrowth and differentiation were also demonstrated. Shh(-/-) mice displayed complete GT agenesis, which is compatible with such observations. Furthermore, the regulation of apoptosis during GT formation was revealed for the first time. Increased cell death and reduced cell proliferation of the Shh(-/-) mice GT were shown. A search for alterations of Shh downstream gene expression identified a dramatic shift of Bmp4 gene expression from the mesenchyme to the epithelium of the Shh mutant before GT outgrowth. Regulation of mesenchymal Fgf10 gene expression by the epithelial Shh was indicated during late GT development. These results suggest a dual mode of Shh function, first by the regulation of initiating GT outgrowth, and second, by subsequent GT differentiation.
Animals↗
The gene encoding the calcium binding protein calcyclin is expressed at sites of exocytosis in the mouse.
Calcyclin is a member of the S100 family of calcium binding proteins. We have found by in situ hybridization that calcyclin transcripts are restricted to specific cell types within a limited number of mouse organs. High levels of expression in the epithelia lining the gastrointestinal, respiratory and urinary tracts, and specific localization of the transcripts to the goblet cells in the small intestine, lead us to suggest a role for calcyclin in the process of mucus secretion. In addition, calcyclin expression was detected in the corpus luteum, placenta and nerves within the gut wall, which are all sites of regulated exocytosis. We propose that this S100-like protein may be part of a calcium signalling pathway utilized in the secretion of various products by different cell types.
Age Factors↗