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J A Weston

Publications and source records attributed to J A Weston.

At least 19 recordsLinked to original sources
PubMed1999

Altered cell-surface targeting of stem cell factor causes loss of melanocyte precursors in Steel17H mutant mice.

The normal products of the murine Steel (Sl) and Dominant white spotting (W) genes are essential for the development of melanocyte precursors, germ cells, and hematopoietic cells. The Sl locus encodes stem cell factor (SCF), which is the ligand of c-kit, a receptor tyrosine kinase encoded by the W locus. One allele of the Sl mutation, Sl17H, exhibits minor hematopoietic defects, sterility only in males, and a complete absence of coat pigmentation. The Sl17H gene encodes SCF protein which exhibits an altered cytoplasmic domain due to a splicing defect. In this paper we analyzed the mechanism by which the pigmentation phenotype in Sl17H mutant mice occurs. We show that in embryos homozygous for Sl17H the number of melanocyte precursors is severely reduced on the lateral neural crest migration pathway by e11.5 and can no longer be detected by e13.5 when they would enter the epidermis in wildtype embryos. The reduced number of dispersing melanocyte precursors correlates with a reduction of SCF immunoreactivity in mutant embryos in all tissues examined. Regardless of the reduced amount, functional SCF is present at the cell surface of fibroblasts transfected with Sl17H mutant SCF cDNA. Since SCF immunoreactivity normally accumulates in basolateral compartments of SCF-expressing embryonic epithelial tissues, we analyzed the localization of wildtype and Sl17H mutant SCF protein in transfected epithelial (MDCK) cells in vitro. As expected, wildtype forms of SCF localize to and are secreted from the basolateral compartment. In contrast, mutant forms of SCF, which either lack a membrane anchor or exhibit the Sl17H altered cytoplasmic tail, localize to and are secreted from the apical compartment of the cultured epithelium. We suggest, therefore, that the loss of melanocyte precursors prior to epidermal invasion, and the loss of germ cells from mature testis, can be explained by the inability of Sl17H mutant SCF to be targeted to the basolateral compartment of polarized epithelial keratinocytes and Sertoli cells, respectively.

Animals↗
PubMed1999

NUMB localizes in the basal cortex of mitotic avian neuroepithelial cells and modulates neuronal differentiation by binding to NOTCH-1.

The importance of lateral inhibition mediated by NOTCH signaling is well demonstrated to control neurogenesis both in invertebrates and vertebrates. We have identified the chicken homolog of Drosophila numb, which suppresses NOTCH signaling. We show that chicken NUMB (c-NUMB) protein is localized to the basal cortex of mitotic neuroepithelial cells, suggesting that c-NUMB regulates neurogenesis by the modification of NOTCH signaling through asymmetrical cell division. Consistent with this suggestion, we show (1) that c-NUMB interferes with the nuclear translocation of activated c-NOTCH-1 through direct binding to the PEST sequence in the cytoplasmic domain of c-NOTCH-1 and (2) that c-NUMB interferes with c-NOTCH-1-mediated inhibition of neuronal differentiation.

Amino Acid Sequence↗
PubMed1998

International multicenter term PROM study: evaluation of predictors of neonatal infection in infants born to patients with premature rupture of membranes at term. Premature Rupture of the Membranes.

OBJECTIVE: Our objective was to determine significant predictors for the development of neonatal infection in infants born to patients with premature rupture of membranes at term. STUDY DESIGN: Multivariate analysis was used to determine the significant predictors of neonatal infection in infants born to women with premature rupture of the membranes who were enrolled in the Term PROM Study. In a randomized, controlled trial, the Term PROM Study recently compared induction of labor with expectant management for premature rupture of membranes at term. RESULTS: The following variables were identified as independent predictors of neonatal infection: clinical chorioamnionitis (odds ratio 5.89, P < .0001), positive maternal group B streptococcal status (vs negative or unknown, odds ratio 3.08, P < .0001), 7 to 8 vaginal digital examinations (vs 0 to 2, odds ratio 2.37, P = .04), 24 to < 48 hours from membrane rupture to active labor (vs < 12 hours, odds ratio 1.97, P = .02), > or = 48 hours from membrane rupture to active labor (vs < 12 hours, odds ratio 2.25, P = .01), and maternal antibiotics before delivery (odds ratio 1.63, P = .05). CONCLUSIONS: Among infants born to patients with premature rupture of membranes at term, clinical chorioamnionitis and maternal colonization with group B streptococci are the most important predictors of subsequent neonatal infection.

Adult↗
PubMed1998

Avian neural crest-derived neurogenic precursors undergo apoptosis on the lateral migration pathway.

Neural crest cells of vertebrate embryos disperse on distinct pathways and produce different derivatives in specific embryonic locations. In the trunk of avian embryos, crest-derived cells that initially migrate on the lateral pathway, between epidermal ectoderm and somite, produce melanocytes but no neuronal derivatives. Although we found that melanocyte precursors are specified before they disperse on the lateral pathway, we also observed that a few crest-derived neuronal cells are briefly present on the same pathway. Here, we show that neuronal cells are removed by an episode of apoptosis. These observations suggest that localized environmental factor(s) affect the distribution of fate-restricted crest derivatives and function as a 'proof-reading mechanism' to remove 'ectopic' crest-derived cells.

Animals↗
PubMed1997

Induction of labour versus expectant management for prelabour rupture of the membranes at term: an economic evaluation. TERMPROM Study Group. Term Prelabour Rupture of the Membranes.

BACKGROUND: As the interval between rupture of the fetal membranes at term and delivery increases, so may the risk of fetal and maternal infection. Recently the TERMPROM (Term Prelabor Rupture of the Membranes) Study Group reported the results of a randomized controlled trial comparing 4 management strategies: induction with oxytocin (IwO), induction with prostaglandin (IwP), and expectant management and induction with either oxytocin (EM-O) or prostaglandin (EM-P) if complications developed. The study found no statistically significant differences in neonatal infection and cesarean section rates between any of the 4 groups. OBJECTIVE: To conduct an economic evaluation comparing the cost of (a) IwO and EM-O, (b) IwP and EM-P and (c) IwO and IwP. DESIGN: An economic analysis, conducted alongside the clinical trial, using a third-party payer perspective. Analysis included all treatment costs incurred for both the mother and the baby. Information on health care utilization and outcomes was collected for all study participants. Three countries (Canada, the United Kingdom and Australia), corresponding to the largest study recruitment, were chosen for calculation of unit costs. For each country, the base, low and high estimates of unit cost for each service item were generated. Intention-to-treat analysis. Extensive statistical and sensitivity analyses were performed. RESULTS: The median cost of IwO per patient was significantly lower statistically than that of EM-O and IwP. This result held in all 3 countries compared -$114 and -$46 in Canada, -113 Pounds and -63 Pounds in the UK, and -A$30 and -A$49 in Australia) and after an extensive sensitivity analysis. There was no statistically significant difference in median cost per patient between IwP and EM-P. CONCLUSION: Although the clinical results of the TERMPROM study did not find IwO to be preferable to the other treatment alternatives, the economic evaluation found it to be less costly. However, these cost differences, even though statistically significant, are not likely to be important in many countries. When this is the case, the authors recommend that women be offered a choice between management strategies.

Australia↗
PubMed1997

Receptor tyrosine kinase-dependent neural crest migration in response to differentially localized growth factors.

How different neural crest derivatives differentiate in distinct embryonic locations in the vertebrate embryo is an intriguing issue. Many attempts have been made to understand the underlying mechanism of specific pathway choices made by migrating neural crest cells. In this speculative review we suggest a new mechanism for the regulation of neural crest cell migration patterns in avian and mammalian embryos, based on recent progress in understanding the expression and activity of receptor tyrosine kinases during embryogenesis. Distinct subpopulations of crestderived cells express specific receptor tyrosine kinases while residing in a migration staging area. We postulate that the differential expression of receptor tyrosine kinases by specific subpopulations of neural crest cells allows them to respond to localized growth factor ligand activity in the embryo. Thus, the migration pathway taken by neural crest subpopulations is determined by their receptor tyrosine kinase response to the differential localization of their cognate ligand.

Animals↗
PubMed1997

International Multicentre Term Prelabor Rupture of Membranes Study: evaluation of predictors of clinical chorioamnionitis and postpartum fever in patients with prelabor rupture of membranes at term.

OBJECTIVES: Our purpose was to determine significant predictors for the development of clinical chorioamnionitis and postpartum fever in patients with prelabor rupture of membranes at term. STUDY DESIGN: Logistic regression analysis with odds ratios and 95% confidence intervals was used to determine the significant predictors of clinical chorioamnionitis and postpartum fever in women with prelabor rupture of membranes at term enrolled in this study. The study recently compared in a randomized controlled trial four strategies of management: induction with oxytocin, induction with prostaglandin, expectant management, and, if failed, induction with oxytocin or prostaglandin. RESULTS: The following variables were significantly associated with clinical chorioamnionitis: (1) number of digital vaginal examinations: > 8, 7 to 8, 5 to 6, 3 to 4 (vs 0 to 2) (odds ratio 5.07, 3.80, 2.62, 2.06); (2) duration of active labor: > or = 12, 9 to < 12, 6 to < 9 hours (vs < 3 hours) (odds ratio 4.12, 2.94, 1.97); (3) meconium-stained amniotic fluid (odds ratio 2.28); (4) parity of 0 (odds ratio 1.80); (5) time from membrane rupture to active labor: > or = 48, 24 to < 48 hours (vs < 12 hours) (odds ratio 1.76, 1.77); and (6) group B streptococcal colonization (odds ratio 1.71). Variables significantly associated with postpartum fever were (1) clinical chorioamnionitis (odds ratio 5.37), (2) duration of active labor: > or = 12, 9 to < 12, 6 to < 9, 2 to < 6 hours (vs < 3 hours) (odds ratio 4.86, 3.53, 3.46, 3.04), (3) cesarean section, operative vaginal delivery (odds ratio 3.97, 1.86), (4) group B streptococcal colonization (odds ratio 1.88), and (5) maternal antibiotics before delivery (odds ratio 1.94). CONCLUSIONS: Increasing numbers of digital vaginal examinations, longer duration of active labor, and meconium staining of the amniotic fluid were the most important risk factors for the development of clinical chorioamnionitis in women with prelabor rupture of membranes at term. The most important risk factors for the development of postpartum fever were clinical chorioamnionitis, increasing duration of active labor, and cesarean section delivery.

Adult↗
PubMed1997

Maternal colonization with group B Streptococcus and prelabor rupture of membranes at term: the role of induction of labor. TermPROM Study Group.

OBJECTIVES: Our purpose was to determine the effect of induction of labor on neonatal infection if mothers are group B streptococci positive and have prelabor rupture of membranes at term. STUDY DESIGN: In the TermPROM study 5041 women were randomized to induction with intravenous oxytocin, induction with vaginal prostaglandin E2 gel, or expectant management with induction, if needed. Of these, 4834 women had vaginal or introital swabs for group B streptococci taken at entry. We used logistic regression to test for effects of treatment within group B streptococci subgroups. RESULTS: Group B streptococci were predictive of neonatal infection for the induction with vaginal prostaglandin E2 gel and expectant groups but not for the induction with oxytocin group. For women positive for group B streptococci the rates of neonatal infection were 2.5% for the induction with oxytocin group and > 8% for all other groups. CONCLUSIONS: Induction of labor with intravenous oxytocin may be preferable for group B streptococci-positive women with prelabor rupture of membranes at term.

Administration, Intravaginal↗
PubMed1997

Women's evaluations of induction of labor versus expectant management for prelabor rupture of the membranes at term. TermPROM Study Group.

BACKGROUND: Induction of labor has become common practice in many Western countries, but few studies have assessed women's views. METHODS: A randomized, controlled trial was conducted at 72 hospitals in six countries. Five thousand forty-one women meeting eligibility criteria, with no contraindications for induction of labor or expectant management, were randomly assigned to four groups: induction with intravenous oxytocin, induction with vaginal prostaglandin E2 gel, or expectant management followed by induction with either oxytocin or with prostaglandin E2 gel if complications developed. The three main outcome measures were evaluations of the treatment received, perceived control during childbirth, and evaluations of the experience of trial participation. RESULTS: Questionnaires were completed by 81.9 percent of the sample. No significant differences occurred between the two induction groups. Compared with the expectant management groups, induced women were less likely to report there was nothing they liked about their treatment and less likely to report that the treatment caused additional worry. No between-group differences occurred in experienced control during childbirth. Women in the induction groups were more likely to be willing to participate in the study again and to feel reassured. CONCLUSIONS: Women's preferences should be considered when making decisions about their method of management when membranes rupture before labor. Obtaining participants' views is both feasible and worthwhile when evaluating forms of medical care.

Adult↗
PubMed1997

Sequential expression and role of Hu RNA-binding proteins during neurogenesis.

We have identified three avian (chicken) Hu/elav family RNA-binding protein genes. cHuD and cHuC are expressed specifically in neurons of both the central and peripheral nervous systems. Although cHuA is expressed in a wide variety of tissues, including neurogenic precursor cells, it is transiently down-regulated, and is then re-expressed in maturing neurons. Misexpression of cHuD in cultured neural crest cells results in a dramatic increase in the proportion of cells exhibiting neuronal morphology, molecular markers for neurons, and neurotrophin dependence. These data confirm that cHuD protein is involved in regulating neuronal differentiation.

3T3 Cells↗
PubMed1997

Timing and pattern of cell fate restrictions in the neural crest lineage.

The trunk neural crest of vertebrate embryos is a transient collection of precursor cells present along the dorsal aspect of the neural tube. These cells migrate on two distinct pathways and give rise to specific derivatives in precise embryonic locations. One group of crest cells migrates early on a ventral pathway and generates neurons and glial cells. A later-dispersing group migrates laterally and gives rise to melanocytes in the skin. These observations raise the possibility that the appearance of distinct derivatives in different embryonic locations is a consequence of lineage restrictions specified before or soon after the onset of neural crest cell migration. To test this notion, we have assessed when and in what order distinct cell fates are specified during neural crest development. We determined the proportions of different types of precursor cells in cultured neural crest populations immediately after emergence from the neural tube and at intervals as development proceeds. We found that the initial neural crest population was a heterogeneous mixture of precursors almost half of which generated single-phenotype clones. Distinct neurogenic and melanogenic sublineages were also present in the outgrowth population almost immediately, but melanogenic precursors dispersed from the neural tube only after many neurogenic precursors had already done so. A discrete fate-restricted neuronal precursor population was distinguished before entirely separate fate-restricted melanocyte and glial precursor populations were present, and well before initial neuronal differentiation. Taken together, our results demonstrate that lineage-restricted subpopulations constitute a major portion of the initial neural crest population and that neural crest diversification occurs well before overt differentiation by the asynchronous restriction of distinct cell fates. Thus, the different morphogenetic and differentiative behavior of neural crest subsets in vivo may result from earlier cell fate-specification events that generate developmentally distinct subpopulations that respond differentially to environmental cues.

Animals↗
PubMed1996

Ectopic c-kit expression affects the fate of melanocyte precursors in Patch mutant embryos.

The Patch (Ph) mutation in the mouse, a deletion that includes the gene for PDGFR alpha, is a recessive lethal that exhibits a dominant pigment phenotype in heterozygotes. To assess whether the Ph mutation acts cell-autonomously or non-autonomously on melanocyte development, we have examined the melanogenic potential of neural crest populations from normal and mutant crest cells in vitro and the pattern of dispersal and survival of melanocyte precursors (MPs) in vivo. We report that trunk neural crest cells from homozygous Ph embryos give rise to pigmented melanocytes in vitro in response to Steel factor (SlF). In vivo, homozygous Ph embryos contain a subpopulation of crest-derived cells that express c-kit and tyrosinase-related protein-2 characteristic of MPs. These cells begin to migrate normally on the lateral crest migration pathway, but then fail to disperse in the dermal mesenchyme and subsequently disappear. Although dermal mesenchyme is adversely affected in Ph homozygotes, SlF mRNA expression by the cells of the dermatome is normal in Ph embryos when neural crest-derived MPs start to migrate on the lateral pathway. In contrast, mRNA for the SlF receptor, c-kit, was observed to be ectopically expressed in somites and lateral mesenchyme in embryos carrying the Ph mutation. Based on this ectopic expression of c-kit in Ph mutant embryos, and the observed distribution of SlF protein in normal and mutant embryos, we suggest that competition for limited amounts of SlF localized on the lateral neural crest migration pathway alters melanocyte dispersal and survival.

Animals↗
PubMed1996

Induction of labor compared with expectant management for prelabor rupture of the membranes at term. TERMPROM Study Group.

BACKGROUND: As the interval between rupture of the fetal membranes at term and delivery increases, so may the risk of fetal and maternal infection. It is not known whether inducing labor will reduce this risk or whether one method of induction is better then another. METHODS: We studied 5041 women with prelabor rupture of the membranes at term. The women were randomly assigned to induction of labor with intravenous oxytocin; induction of labor with vaginal prostaglandin E2 gel; or expectant management for up to four days, with labor induced with either intravenous oxytocin or vaginal prostaglandin E2 gel if complications developed. The primary outcome was neonatal infection. Secondary outcomes were the need for cesarean section and women's evaluations of their treatment. RESULTS: The rates of neonatal infection and cesarean section were not significantly different among the study groups. The rates of neonatal infection were 2.0 percent for the induction-with-oxytocin group, 3.0 percent for the induction-with-prostaglandin group, 2.8 percent for the expectant-management (oxytocin) group, and 2.7 percent for the expectant-management (prostaglandin) group. The rates of cesarean section ranged from 9.6 to 10.9 percent. Clinical chorioamnionitis was less likely to develop in the women in the induction-with-oxytocin group than in those in the expectant-management (oxytocin) group (4.0 percent vs. 8.6 percent, P<0.001), as was postpartum fever (1.9 percent vs. 3.6 percent, P=0.008). Women in the induction groups were less likely to say they liked "nothing" about their treatment than those in the expectant-management groups. CONCLUSIONS: In women with prelabor rupture of the membranes at term, induction of labor with oxytocin or prostaglandin E2 and expectant management result in similar rates of neonatal infection and cesarean section. Induction of labor with intravenous oxytocin results in a lower risk of maternal infection than does expectant management. Women view induction of labor more positively than expectant management.

Adult↗
PubMed1996

Screen for mutations affecting development of Zebrafish neural crest.

The neural crest provides a useful model to learn how cell fate diversification is regulated during vertebrate development. Our approach is to isolate zebrafish mutations in which the development of neural crest derivatives is disrupted, in order to learn about the underlying genetic mechanisms. We describe a screen in which parthenogenetic diploid embryos are examined both for visible phenotypes and for cellular defects in neural crest-derived sensory neurons recognized immunohistochemically. We present preliminary results from this screen and briefly describe a few representative mutations. We also discuss the general utility of our strategy and comment on the future directions of this approach.

Animals↗
PubMed1995

Novel FGF receptor (Z-FGFR4) is dynamically expressed in mesoderm and neurectoderm during early zebrafish embryogenesis.

We have identified a novel FGF receptor, Z-FGFR4, in zebrafish embryos. Z-FGFR4 is closely related to both chicken FREK (Marcelle et al. [1994] Development 120:683-694) and the Pleurodeles cDNA clone Pw-FGFR4 (also named PFR4). The Z-FGFR4 cDNA clones contain consensus sequences for two groups of two Ig-like domains, separated by eight acidic residues referred to as the "acid box." Z-FGFR4, therefore, is the first FGFR molecule yet described in vertebrates that contains four Ig domains in its amino-terminal region. Whole-mount in situ hybridization of staged zebrafish embryos, using probes prepared from a variety of domains of the Z-FGFR4 cDNA, reveal complex temporal and spatial expression patterns. Expression of Z-FGFR4 mRNA is first detected in embryos prior to gastrulation and then appears in prechordal plate mesendoderm. At this time, Z-FGFR mRNA is expressed in the epiblast in two distinct stripes which ultimately contribute to the brain. Eventually Z-FGFR4 transcripts are observed in forebrain, anterior hindbrain (rhombomeres 1, 3), and caudal hindbrain (rhombomere 7), as well as in the dorsal-most portion of the rostral spinal cord. Expression in axial mesendoderm appears transiently in notochord and segmental plate mesoderm. Eventually, Z-FGFR4 mRNA becomes restricted to the posterior somites and is absent in differentiated notochord. These detailed expression studies provide the basis for understanding FGFR function through an analysis, currently in progress, of the developmental consequences of Z-FGFR4 misexpression.

Animals↗
PubMed1995

Genetic control of adult pigment stripe development in zebrafish.

Adult zebrafish stripes are formed from stripes of gold iridophores alternating with stripes of black melanocytes lying beneath silver stripes. Analysis of defects in pigment pattern development caused by sparse (spa, rose (ros), and leopard (leo) single and double mutant combinations suggests that spa+ and ros+ functions are required for development of separate populations of pigment cells in the adult and that leo+ functions to control assembly of melanocytes into stripes. Thus, between 2 and 3 weeks of zebrafish development, spa-dependent melanocytes differentiate throughout the flank, followed by leo-dependent assembly of these cells into stripes. Beginning at 3 weeks of development, a distinct ros-dependent population of melanocytes differentiates in the stripe. Both early and late differentiating melanocytes then affect the formation of the silver stripes, ensuring registration of melanocyte and iridophore stripes.

Animals↗