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The possible involvement of prolactin (PRL) and growth hormone (GH) in osmoregulation during early life stages of the tilapia (Oreochromis mossambicus) was examined by in situ hybridization and immunocytochemistry using synthetic oligonucleotide probes and homologous antisera to two tilapia PRLs (PRL188 and PRL177) and GH. Hybridization signals for PRL188 mRNA were detected for the first time in newly hatched larvae (5 days after fertilization), and were significantly greater in larvae in fresh water (FW) than those in seawater (SW) until 10 days after hatching. PRL177 mRNA was detected in the pituitary of embryos 1 day before hatching. Although PRL177 gene expression in the embryo and newly hatched larvae in FW was not significantly different from those in SW, the expression was significantly greater in FW than in SW from Day 2 until Day 10. Hybridization signals for GH mRNA were first detected in newly hatched larvae. No significant differences in GH mRNA expression were observed between larvae in FW and those in SW. A stronger immunoreaction, a significantly larger PRL cell size, and a pituitary area containing PRL cells were observed in larvae hatched and maintained in FW, in those transferred from SW to FW, compared to larvae hatched and maintained in SW, and in those transferred from FW to SW. No significant difference was observed in the activity of GH cells between larvae in FW and those in SW. These results suggest that both PRLs are involved importantly in FW adaptation, whereas GH does not seem to play a critical role in osmoregulation during early stages of tilapia.
To identify the early renal lesions in cystinosis, including whether the "swan neck" deformity of the proximal tubule is a congenital or an acquired lesion, we performed renal function tests and kidney biopsies on two cystinotic infants, on one at 5 and 14 months and on the other at 6 and 12 months of age. The "swan neck" deformity appears to be an acquired lesion for two reasons. First, the characteristic thin neck of the proximal tubule was not demonstrated by nephron microdissection or light microscopy until after 6 months of life. Second, electron microscopy revealed that prior to the development of the lesion, the tubular cells in the neck region of the proximal tubule were undergoing degenerative changes. Renal function tests indicated that the manifestations of the Fanconi syndrome correlated with the stages of development of the "swan neck" lesion. Minute crystalline spaces having some of the characteristics of lysosomal cystine crystals appeared in the early biopsies only in that portion of the proximal tubule which was undergoing atrophy to form the "swan neck" lesion observed in the later biopsies. These findings provide evidence of at least a temporal relationship between apparent cellular cystine accumulation and the development of the "swan neck" lesion and the Fanconi syndrome.
Oxytocin (OT) prohormone processing was studied in fetal sheep. Using specific antisera that recognize the amidated and the COOH-terminal extended forms of OT, we measured arterial and venous levels of the OT peptides in fetal sheep plasma at 94 and 138 days of gestation. Plasma levels of the COOH-terminal extended forms, OT-X, were highest early in development, 35.7 +/- 9.8 vs. 14.3 +/- 5.7 pg/ml (94 vs. 138 days). The ratio of the plasma peptides, OT-X to OT, was higher in the young fetus (35 +/- 11.6 vs. 3.1 +/- 1.3, 94 vs. 138 days). There were also developmental changes in the umbilical artery-umbilical vein differences, with positive values noted in late gestation. These results demonstrate that the changes in the processing of the OT precursor that occur during fetal development are reflected by alterations in the relative amounts of prohormone and amidated hormone found in fetal plasma.
Rat embryos were explanted on late 11 day of gestation and cultured for 24 hours in rotating bottles with the yolk sac opened. Rat serum was used as culture medium and culture bottles were filled with 5% CO2 + 95% O2 gas mixture as gas phase. At the time of explantation and the end of the culture period, differentiation and growth of the embryos were monitored by counting somites and measuring crown rump length. About part of the embryos, protein determinations were made to measure growth. These data were compared with values found for 12 and 13 day embryos. The results for cultured embryos showed slight retardation in their differentiation and slight depression in the growth. At the same time to study early inner ear development in vitro, 9 of the other cultured embryos were serially sectioned and observed by light microscopy. In the cultured embryos endolymphatic duct elongated and acoustico-facial ganglion enlarged remarkably. Otocysts became flattened and elongated ventrally. Vestibular and cochlear portion were identifiable in the otocysts. Nerves arose from the ganglion reached to brain centrally and wall of pharynx peripherally. There was no significant difference in inner ear development between 13 day and the cultured embryos. This culture system should prove useful for studies on early inner ear development of mammalian embryos.
In zebrafish, many nerve pathways in both the CNS and periphery are pioneered by a small and relatively simple set of 'primary' neurons that arise in the early embryo. We now have used monoclonal antibodies to show that, as they develop, primary neurons of several functional classes express on their surfaces the L2/HNK-1 tetrasaccharide that is associated with a variety of cell surface adhesion molecules. We have studied the early labeling patterns of these neurons, as well as some non-neural cells, and found that the time of onset and intensity of immunolabeling vary specifically according to cell type. The first neuronal expression is by Rohon-Beard and trigeminal ganglion neurons, both of which are primary sensory neurons that mediate touch sensitivity. These cells express the epitope very strongly on their growth cones and axons, permitting study of their development unobscured by labeling in other cells. Both types initiate axogenesis at the same early time, and appear to be the first neurons in the embryo to do so. Their peripheral neurites display similar branching patterns and have similar distinctive growth cone morphologies. Their central axons grow at the same rate along the same longitudinal fiber pathway, but in opposite directions, and where they meet they appear to fasciculate with one another. The similarities suggest that Rohon-Beard and trigeminal ganglion neurons, despite their different positions, share a common program of early development. Immunolabeling is also specifically present on a region of the brain surface where the newly arriving trigeminal sensory axons will enter the brain. Further, the trigeminal expression of the antigen persists in growth cones during the time that they contact an individually identified central target neuron, the Mauthner cell, which also expresses the epitope. These findings provide descriptive evidence for possible roles of L2/HNK-1 immunoreactive molecules in axonal growth and synaptogenesis.
Embryos of the toad, Bufo arenarum, Hensel, taken during early stages of development were used to survey the [U-14C]glycerol and 32P lipid labeling. When precursors were supplied at the time of oogenesis, large differences in specific activities of phospholipid were observed. Using 32P, a steep rise as a function of development was evidenced. Triglycerides contained much higher proportions of [U-14C] glycerol than phospholipids when administered to the female toad along with a pituitary homogenate. However, lack of [U-14 C] glycerol uptake into lipids was observed when cell-free homogenates of eggs at different stages of development ranging from unfertilized oocyte to midgastrula were incubated in unsupplemented amphibian Ringer. At the later stage, significant de novo biosynthesis of lipids from glycerol began to be measurable, whereas during cell cleavage intracellular redistribution of preformed phosphoglycerides was used for membrane assembly.
The relationship between early sexual maturation and the psychosexual behaviors of dating and sexual intercourse was investigated using a national sample of adolescent females aged 15 to 19. Among both black and nonblack subjects, early-maturing girls were more likely to have experienced earlier dating and coital onset than were their later-maturing peers. Blacks experienced menarche and first intercourse at earlier ages, yet dating onset at later ages. Early menarche was also associated with marriage at an early age for nonblacks, but not for blacks. These racial differences were explained in terms of diverse socialization patterns or cultural expectations. For both blacks and nonblacks, those with earlier coital experience were found to have had menarche and dating onset at earlier ages.
Children diagnosed as congenitally hypothyroid and treated from a very early age were followed up at 1 and 3 years. At 1 year they seemed to be developing normally, unless they were undertreated or had an additional disorder. There were no significant correlations between biochemical or social factors and psychological outcome at 1 year. At 3 years, however, those children whose T4 and/or T3 had been very low initially had significantly lower IQ scores than both other hypothyroid children and matched controls. Children with only moderately low initial T4 and/or T3, however, were doing just as well as their matched controls. Initial levels of TSH, the number of symptoms at first clinical interview and the age at the start of treatment were not good indicators of ability at 3 years. Undertreatment was rare but did appear to affect ability. Psychological outcome at 3 years was also correlated with social class (for both cases and controls). Multiple regression analyses indicated that both low initial T4 (less than 20 nmol/l) and social class contributed significantly to outcome.
A growing number of environmental toxicants found in pesticides, herbicides, and industrial solvents are believed to have deleterious effects on development by disrupting hormone-sensitive processes. We exposed Xenopus laevis embryos at early gastrula to the commonly encountered environmental estrogens nonylphenol, octylphenol, and methoxychlor, the antiandrogen, p,p-DDE, or the synthetic androgen, 17 alpha-methyltestosterone at concentrations ranging from 10 nM to 10 microM and examined them at tailbud stages (approximately 48 hr of treatment). Exposure to the three environmental estrogens, as well as to the natural estrogen 17 beta-estradiol, increased mortality, induced morphologic deformations, increased apoptosis, and altered the deposition and differentiation of neural crest-derived melanocytes in tailbud stage embryos. Although neural crest-derived melanocytes were markedly altered in embryos treated with estrogenic toxicants, expression of the early neural crest maker Xslug, a factor that regulates both the induction and subsequent migration of neural crest cells, was not affected, suggesting that the disruption induced by these compounds with respect to melanocyte development may occur at later stages of their differentiation. Co-incubation of embryos with the pure antiestrogen ICI 182,780 blocked the ability of nonylphenol to induce abnormalities in body shape and in melanocyte differentiation but did not block the effects of methoxychlor. Our data indicate not only that acute exposure to these environmental estrogens induces deleterious effects on early vertebrate development but also that different environmental estrogens may alter the fate of a specific cell type via different mechanisms. Finally, our data suggest that the differentiation of neural crest-derived melanocytes may be particularly sensitive to the disruptive actions of these ubiquitous chemical contaminants.
The plainfin midshipman fish (Porichthys notatus) has a caudal hindbrain vocal motor circuit that has been proposed to share a common embryonic origin with the hindbrain vocal networks of other vertebrates. In midshipman, this vocal circuit includes three groups of neurons: sonic motor, pacemaker, and ventral medullary. Here, transneuronal transport of biocytin or neurobiotin was used to delineate the early ontogeny of the three hindbrain vocal nuclei and their pattern of connectivity. The organization of the vocal nuclei was studied in animals beginning soon after hatching until the nuclei have the adult phenotype at the time fish become free-swimming. There is a clear sequence of events whereby motoneurons establish their connections with the sonic muscle prior to establishing connections with premotor neurons; developmental milestones of the vocal pathway parallel those of the sonic muscle. The results also indicate that sexual differentiation of the vocal motor system in midshipman begins early in development, well before any evidence of sexual maturation. Embryonic males and females differ in the relationship between soma size and body length for the three hindbrain nuclei. Males are also more variable than females in body mass, volume of the sonic motor nucleus, and motoneuron cell size.
We investigated the relationship between emotional changes, brain lesion burden and development of multiple sclerosis (MS). Thirty-seven consecutive patients with clinically isolated syndrome (CIS) were prospectively assessed with the Expanded Disability Status Scale (EDSS), the 21-item Beck Depression Inventory (BDI), the State-Trait Anxiety Inventory (STAI) and gadolinium enhanced (Gd+) MRI scans. BDI and STAI were also administered to 36 age-matched controls. Conversion to MS was defined as the occurrence of a clinical relapse. CIS patients were more likely to endorse symptoms of anxiety and depression than controls. Baseline scores for depression and anxiety did not correlate with the total lesion load (i.e., volume of Gd+, T2 and T1 lesions) and the number of Gd+ lesions during the first six months of follow-up. A positive correlation was found between severity of depressive scores and the lesion load in the right temporal region (P = 0.005). After 33+/-6 months of the study entry, patients who had a clinical relapse were more frequently depressed (P = 0.001) than those relapse free. Emotional disturbances are frequently observed in CIS patients and show a tendency towards a normalization in relapse-free patients. The increased rate of depressive symptoms observed in patients who developed MS seems to result from a combination of psychological and organic features. The lesion load in the right temporal region is confirmed as a key area for developing depressive symptoms, even in the early phase of the disease.
Hypoxia Inducible Factor (HIF), consisting of HIF1alpha and ARNT (HIF1beta) subunits, activates multiple genes in response to oxygen (O(2)) deprivation. Arnt(-/-) mice exhibit substantial defects in blood cell and vessel development. We demonstrate that hypoxia accelerates the expression of Brachyury (a mesoderm-specific transcription factor), BMP4 (a mesoderm-promoting growth factor) and FLK1 (a marker of hemangioblasts, the bipotential progenitor of endothelial and hematopoietic cells) in differentiating ES cell cultures. Significantly, proliferation of embryonic hemangioblasts (BL-CFCs) is regulated by hypoxia, as Arnt(+/+) ES cells generate increased numbers of FLK1(+) cells, and BL-CFCs with accelerated kinetics in response to low O(2). This response is HIF-dependent as Arnt(-/-) ES cells produce fewer FLK1(+) cells and BL-CFCs, under both normoxic and hypoxic conditions. Interestingly, this defect is rescued when Arnt(-/-) ES cells are co-cultured with Arnt(+/+) ES cells. Vegf(+/-)or Vegf(-/-) ES cells generate proper numbers of FLK1(+) cells but fewer BL-CFCs, suggesting that additional factors regulated by HIF (other than VEGF) are involved in these early events. Thus, hypoxic responses are important for the establishment of various progenitor cells, including early mesoderm and its differentiation into hemangioblasts. Together these data suggest that ineffective responses to hypoxia in Arnt(-/-) embryos abrogate proper cardiovascular development during early embryogenesis, including the pathways controlling hemangioblast differentiation.
stella is a novel gene specifically expressed in primordial germ cells, oocytes, preimplantation embryos, and pluripotent cells. It encodes a protein with a SAP-like domain and a splicing factor motif-like structure, suggesting possible roles in chromosomal organization or RNA processing. Here, we have investigated the effects of a targeted mutation of stella in mice. We show that while matings between heterozygous animals resulted in the birth of apparently normal stella null offspring, stella-deficient females displayed severely reduced fertility due to a lack of maternally inherited Stella-protein in their oocytes. Indeed, we demonstrate that embryos without Stella are compromised in preimplantation development and rarely reach the blastocyst stage. stella is thus one of few known mammalian maternal effect genes, as the phenotypic effect on embryonic development is mainly a consequence of the maternal stella mutant genotype. Furthermore, we show that STELLA that is expressed in human oocytes is also expressed in human pluripotent cells and in germ cell tumors. Interestingly, human chromosome 12p, which harbours STELLA, is consistently overrepresented in these tumors. These findings suggest a similar role for STELLA during early human development as in mice and a potential involvement in germ cell tumors.
It is established that in embryos incubated until the early blastula stage in the solution of insulin with addition of cycloheximide or puromycin, there is neither a decrease in the hexokinase and glucose-61 phosphate dehydrogenase activities nor an increase in the phosphofructokinase activity, as it is shown under the influence of insulin only. Puromycin removes an inhibitory effect of insulin on the glucose-6-phosphatase activity, and actinomycin D removes this influence with respect to glucose-6-phosphate dehydrogenase and glucose-6-phosphatase activities. The addition of antibiotics removes inhibition of the hexokinase, glucose-6-phosphate dehydrogenase and glucose-6-phosphatase activities by the hormone in the unfertilized eggs as well. Actinomycin D alone inhibits the hexokinase and activates the phosphofructokinase activities in the embryos and eggs, puromycin decreases their hexokinase activity and cycloheximide has the same effect on the glucose-6-phosphatase activity in the embryos only.
Environmental influences on the developing primary visual cortex of kittens were studied by exposing dark reared kittens to prism-induced interocular rotational disparities of 32 degrees, the visual input rotated equally and oppositely in the two eyes. The present report describes preliminary results obtained from two kittens that received this altered visual exposure during 1-6 hours each day from 4 until 12 weeks of age. Subsequent single-unit recordings from the striate cortex revealed three major changes in functional cortical visual physiology. First, there was a disruption in binocularity, with many more cells being monocularly driven in the rotated conditions compared to control conditions. Second, there was an increased variance in the distribution of cells' interocular differences in preferred stimulus orientation (interocular orientation disparity, or IOD) as compared to control conditions. Third, changes were noted in orientation tuning and in the distribution of orientation preferences: cells most selective for orientation tended to be in the extreme ocular dominance groups, and monocular cells were often the most highly selective; also, both binocular and monocular cells showed a tendency for preferred orientations for both eyes to fall near the horizontal or vertical (+/- 22.5 degrees). Thus, a large optically-induced orientation disparity between the two eyes' visual fields during the critical period can modify the characteristics of striate cortical neurons, particularly binocularity and IOD. In addition, these results indicate that an inherent cortical mechanism may ensure the encoding of horizontal and vertical orientation specificities for a subclass of primary visual cortical neurons.
Certain endogenous Xenopus mRNAs, carrying a destabilizing 3' AU-rich sequence, are unusually very stable in oocytes and become unstable only after fertilization. In addition, heterologous short lived mRNA, containing 3' AU-rich sequences, appear to be very stable when injected into Xenopus oocytes. In the present study, a human interferon beta (hu-IFN beta) mRNA, carrying the destabilizing 3' AU-rich element, was used as a probe to identify Xenopus proteins that specifically bind to the 3' AU-rich element as well as to study their relative levels during early embryonic development. While three major proteins that specifically bind to the 3' AU-rich element were detected in human SV80 cells, that naturally express hu-IFN beta (proteins termed AU-F1, F2 and F3), only two proteins, migrating similarly to the SV80 AU-F1 and AU-F3, were detected in cytoplasmic extracts from Xenopus oocytes or eggs. Following fertilization, the intensity of the Xenopus AU-F1 and AU-F3 proteins increased considerably and a new protein, corresponding to SV80 AU-F2, was also detected. Cyclohexamide applied either at the morula or at the early blastula stages reduced the intensity of the AU-binding factors, while actinomycin D did not, indicating that the levels of these factors during these stages are regulated posttranscriptionally. In contrast, application of each of these metabolic inhibitors at the late blastula stage increased the intensity of the AU-binding proteins. The possible function of these AU-binding factors in regulating the expression and half life of AU-rich mRNAs is discussed.
BACKGROUND: Cdc42 and other Rho GTPases are conserved from yeast to humans and are thought to regulate multiple cellular functions by inducing coordinated changes in actin reorganization and by activating signaling pathways leading to specific gene expression. Direct evidence implicating upstream signals and components that regulate Cdc42 activity or for required roles of Cdc42 in activation of downstream protein kinase signaling cascades is minimal, however. Also, whereas genetic analyses have shown that Cdc42 is essential for cell viability in yeast, its potential roles in the growth and development of mammalian cells have not been directly assessed. RESULTS: To elucidate potential functions of Cdc42 mammalian cells, we used gene-targeted mutation to inactivate Cdc42 in mouse embryonic stem (ES) cells and in the mouse germline. Surprisingly, Cdc42-deficient ES cells exhibited normal proliferation and phosphorylation of mitogen- and stress-activated protein kinases. Yet Cdc42 deficiency caused very early embryonic lethality in mice and led to aberrant actin cytoskeletal organization in ES cells. Moreover, extracts from Cdc42-deficient cells failed to support phosphatidylinositol 4,5-bisphosphate (PIP(2))-induced actin polymerization. CONCLUSIONS: Our studies clearly demonstrate that Cdc42 mediates PIP(2)-induced actin assembly, and document a critical and unique role for Cdc42 in this process. Moreover, we conclude that, unexpectedly, Cdc42 is not necessary for viability or proliferation of mammalian early embryonic cells. Cdc42 is, however, absolutely required for early mammalian development.