Changes in the pattern of twisted gastrulation gene expression among Drosophila species.

A long-standing hypothesis posits that morphological changes may be more likely to result from changes in regulation of gene expression than from changes in the protein coding sequences of genes. We have compared the expression pattern of the twisted gastrulation (tsg) gene among five Drosophila species: D. melanogaster, D. simulans, D. subobscura, D. mojavensis, and D. virilis. The tsg gene encodes a secreted protein that is required for the specification of dorsal midline fates in the Drosophila early embryo. TSG is unlike other secreted growth and differentiation factors in Drosophila in that its expression pattern can be experimentally varied and still result in normal development. Because of this, its regulatory region may be freer to diverge than that of other developmental genes whose misexpression may lead to lethal defects. Thus, the tsg gene may be a good indicator of the frequency and nature of evolutionary changes affecting patterns of gene expression. Over approximately 60 million years (Myr), the tsg gene has retained a dorsal-on/ventral-off pattern and a middorsal region of expression; but there have been marked changes in the middorsal domain of expression as well as the appearance/loss of other domains of expression along the anterior/posterior axis. Changes between closely related species (approximately 2-5 Myr since divergence) that are not reflected among more distantly related species suggest frequent changes in gene expression over evolutionary time. These changes in gene expression may serve as the raw material for eventual evolutionary changes in morphology.

Combinatorial signaling by Twisted Gastrulation and Decapentaplegic.

The Twisted Gastrulation (TSG) protein is one of five secreted proteins required to pattern the dorsal part of the early Drosophila embryo. Unlike the Decapentaplegic (DPP) protein that is required to pattern the entire dorsal half of the embryo, TSG is needed only to specify the fate of the dorsal midline cells. Here we have misexpressed the tsg gene with different promoters to address its mechanism of action and relationship to DPP. When expressed in a ventral stripe of cells, TSG protein can diffuse to the dorsalmost cells and can rescue the dorsal midline cells in tsg mutant embryos. Despite elevated levels that exceed that exceed those needed for biological activity, there was no change in dorsal midline or lateral cell fates under any conditions tested. We conclude that TSG does not modulate an activity gradient of DPP. Instead, it functions in a permissive rather than instructive role to elaborate cell fates along the dorsal midline after peak levels of DPP activity have 'primed' cells to respond to TSG. The interaction between TSG and DPP defines a novel type of combinatorial synergism.

Dorsal midline fate in Drosophila embryos requires twisted gastrulation, a gene encoding a secreted protein related to human connective tissue growth factor.

The twisted gastrulation (tsg) gene is one of seven known zygotic genes that specify the fate of dorsal cells in Drosophila embryos. Mutations in these genes cause at least some of the cells on the dorsal half of the embryo to adopt more ventral cell fates leading to the proposal that most of these genes participate in establishing, maintaining, or modulating a gradient of a single signaling molecule DECAPENTAPLEGIC (DPP). We have examined the effects of tsg mutations on the development of cuticule elements, expression of a region specific enhancer trap, and patterns of mitotic domains. Mutations of tsg only affect the fate of a narrow strip of dorsal midline cells and do not affect dorsal ectoderm cells. However, the pattern of tsg expression is not coincident with the territories affected by tsg mutations. Structural analysis of the tsg gene reveals features of a secreted protein suggesting an extracellular site of action. The TSG protein bears a weak resemblance to human connective tissue growth factor (CTGF), a TGF-beta-induced protein. We propose that dorsal midline cell fate is specified by the combination of both a TSG and a DPP signal to which the dorsal midline cells are uniquely competent to respond.

The relationship between exposure during pregnancy to cigarette smoking and cocaine use and placenta previa.

OBJECTIVE: This study examined the relationship between two maternal exposures, cigarette smoking and cocaine use, and placenta previa. STUDY DESIGN: A hospital-based case-control study was conducted. Three hundred four cases of placenta previa were compared with 2732 controls with respect to demographic characteristics, substance use, and perinatal characteristics. Logistic regression was used to examine the individual effects of cigarette smoking and cocaine use on placenta previa, independent of other known risk factors. RESULTS: A dose-response relationship between smoking cigarettes and placenta previa was observed independent of other known risk factors (ptrend < 0.01). Pregnant women who smoked > or = 20 cigarettes per day were over two times more likely to experience a placenta previa relative to nonsmokers (odds ratio 2.3, 95% confidence interval 1.5 to 3.5). Pregnant women who used cocaine were 1.4 times (95% confidence interval 0.8 to 2.4) as likely to experience a placenta previa as nonusers. CONCLUSIONS: The previously observed association between smoking and placenta previa is supported by the dose-response relationship observed in this study. The potential association of cocaine with placenta previa needs more exploration.

Effects of magnesium infusions on magnesium and nitrogen balance during parenteral nutrition.

The effects of magnesium infusions on urinary and fecal magnesium excretion, serum magnesium and nitrogen balance were examined in seven well-nourished and three nutritionally depleted adult surgical patients receiving total parenteral nutrition. They were maintained on constant nitrogen and caloric intake for 14 +/- 2 days. Magnesium doses ranged from 0 to 664 mg/d and were given in varying crossover patterns. In both groups, urinary magnesium excretion increased as the amount of magnesium infused increased but, at comparable magnesium infusions, depleted patients excreted significantly less magnesium. Renal conservation was most pronounced in well-nourished patients on magnesium-free intake and in depleted patients given 70 mg magnesium daily. Urinary magnesium losses were 40 +/- 5 mg/d and 33 +/- 8 mg/d, respectively, in these two groups. Endogenous fecal magnesium excretion was minimal and ranged from 2 to 38 mg/d. At each level of magnesium intake, serum levels of well-nourished patients were normal. With infusions of less than 200 mg/d, serum magnesium concentrations in depleted subjects averaged 1.6 mg/dl. Reduced urinary magnesium excretion as well as borderline serum levels measured in depleted adults suggest that the magnesium dosage should be higher than that usually recommended during total parenteral nutrition. In both groups a positive correlation between magnesium and nitrogen balance was noted.