Metastasis is a frequent and lethal complication of cancer. Vascular endothelial growth factor‐C (VEGF‐C) is a recently described lymphangiogenic factor. Increased expression of VEGF‐C in primary tumours correlates with dissemination of tumour cells to regional lymph nodes. However, a direct role for VEGF‐C in tumour lymphangiogenesis and subsequent metastasis has yet to be demonstrated. Here we report the establishment of transgenic mice in which VEGF‐C expression, driven by the rat insulin promoter (Rip), is targeted to β‐cells of the endocrine pancreas. In contrast to wild‐type mice, which lack peri‐insular lymphatics, RipVEGF‐C transgenics develop an extensive network of lymphatics around the islets of Langerhans. These mice were crossed with Rip1Tag2 mice, which develop pancreatic β‐cell tumours that are neither lymphangiogenic nor metastatic. Double‐transgenic mice formed tumours surrounded by well developed lymphatics, which frequently contained tumour cell masses of β‐cell origin. These mice frequently developed pancreatic lymph node metastases. Our findings demonstrate that VEGF‐C‐induced lymphangiogenesis mediates tumour cell dissemination and the formation of lymph node metastases.

The translational activation of dormant tissue-type plasminogen activator mRNA during meiotic maturation of mouse oocytes is accompanied by elongation of its 3'-poly(A) tract. Injected RNA fragments that correspond to part of the 3'-untranslated region (3'UTR) of this mRNA are also subject to regulated polyadenylation. Chimeric mRNAs containing part of this 3'UTR are polyadenylated and translated following resumption of meiosis. Polyadenylation and translation of chimeric mRNAs require both specific sequences in the 3'UTR and the canonical 3'-processing signal AAUAAA. Injection of 3'-blocked mRNAs and in vitro polyadenylated mRNAs shows that the presence of a long poly(A) tract is necessary and sufficient for translation. These results establish a role for regulated polyadenylation in the post-transcriptional control of gene expression.

The serine protease tissue-type plasminogen activator (t-PA) is synthesized by murine oocytes undergoing meiotic maturation, but not by arrested primary oocytes. Dormant, stable t-PA mRNA accumulates during oocyte growth, so that fully grown, arrested primary oocytes contain in their cytoplasm approximately 10,000 copies of this molecule. Translation of t-PA mRNA is triggered upon resumption of meiosis and is accompanied by a progressive and concerted increase in its size. This structural change can be accounted for by increased polyadenylation at the 3' end of the molecule. Following its translation, t-PA mRNA is degraded; it is no longer detectable in fertilized eggs. The identification of a dormant mRNA in murine oocytes and the demonstration that its translational activation is accompanied by elongation of its poly(A) tail may provide insights into the control of gene expression during meiotic maturation and early mammalian development.

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The mechanisms responsible for translational silencing of certain mRNAs in growing oocytes, and for their awakening during meiotic maturation, are not completely elucidated. We show that binding of a ∼80-kD protein to a UA-rich element in the 3 UTR of tissue-type plasminogen activator mRNA, a mouse oocyte mRNA that is translated during meiotic maturation, silences the mRNA in primary oocytes. Translation can be triggered by injecting a competitor transcript that displaces this silencing factor, without elongation of a pre-existing short poly(A) tail, the presence of which is mandatory. During meiotic maturation, cytoplasmic polyadenylation is necessary to maintain a poly(A) tail, but the determining event for translational activation appears to be the modification or displacement of the silencing factor.

Targeted disruption of mouse ␤ 3 -adrenoceptor was generated by homologous recombination, and validated by an acute in vivo study showing a complete lack of effect of the ␤ 3 -adrenoceptor agonist CL 316,243 on the metabolic rate of homozygous null ( Ϫ / Ϫ ) mice. In brown adipose tissue, ␤ 3 -adrenoceptor disruption induced a 66% decrease ( P Ͻ 0.005) in ␤ 1 -adrenoceptor mRNA level, whereas leptin mRNA remained unchanged. Chronic energy balance studies in chow-fed mice showed that in Ϫ / Ϫ mice, body fat accumulation was favored ( ϩ 41%, P Ͻ 0.01), with a slight increase in food intake ( ϩ 6%, NS). These effects were accentuated by high fat feeding: Ϫ / Ϫ mice showed increased total body fat ( ϩ 56%, P Ͻ 0.025) and food intake ( ϩ 12%, P Ͻ 0.01), and a decrease in the fat-free dry mass ( Ϫ 10%, P Ͻ 0.05), which reflects a reduction in body protein content. Circulating leptin levels were not different in Ϫ / Ϫ and control mice regardless of diet. The significant shift to the right in the positive correlation between circulating leptin and percentage of body fat in high fat-fed Ϫ / Ϫ mice suggests that the threshold of body fat content inducing leptin secretion is higher in Ϫ / Ϫ than in control mice. Taken together, these studies demonstrate that ␤ 3 -adrenoceptor disruption creates conditions which predispose to the development of obesity. ( J. Clin. Invest. 1997. 100:1098-1106.)

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SummaryMice bearing a tumor necrosis factor (TNF) ot transgene controlled by an insulin promoter developed an increasingly severe lymphocytic insulitis, apparently resulting from the induction of endothelial changes with features similar to those observed in other places of intense lymphocytic traffic. This was accompanied by dissociation of the endocrine tissue (without marked decrease in its total mass), islet fibrosis, and the development of intraislet ductules containing, by places, cells in their walls, suggesting a regenerative capacity. Islet disorganization and fibrosis did not result from lymphocytic infiltration, since they were also observed in SCID mice bearing the transgene. Diabetes never developed, even though a number of potentially inducing conditions were used, including the prolonged perfusion of interferon 3' and the permanent expression of a nontolerogenic viral protein on/3 cells (obtained by using mice bearing two transgenes). It is concluded that (a) a slow process of TNF release in pancreatic islets induces insulitis, and may be instrumental in the insulitis resulting from local cell-mediated immune reactions, but (b) that insulitis per se is not diabetogenic, lymphocyte stimulation by cells other than B cells being necessary to trigger extensive B cell damage. This provides an explanation for the discrepancy between the occurrence of insulitis and that of clinical disease in autoimmune diabetes.