The M variant of encephalomyocarditis (EMC) 1 virus produces a diabetes-like syndrome in mice by infecting and destroying pancreatic beta cells (1-3). The severity of the diabetes correlates with the degree of virus-induced beta cell damage (4, 5). Only certain inbred strains of mice develop diabetes, and susceptibility to EMC virusinduced diabetes is inherited as an autosomal recessive trait (2, 6-8). The genetic factors controlling susceptibility operate at the level of the beta cell, and whether a particular strain of mouse develops diabetes appears to be related to differences in the permissiveness of beta cells to infection with EMC virus (9, 10).Previous experiments (5) showed that when mice were inoculated with a high concentration of mouse-passaged EMC virus (10 8 plaque-forming units [PFU]), fewer animals developed diabetes than when inoculated with a low concentration of the same virus (10 ~ PFU). Moreover, the diabetogenic capacity of the virus was markedly diminished after passage in mouse fibroblast cultures, but was restored when passaged in mice. This raised the possibility that the stock pool of EMC virus was made up of two populations of virus: one that had a tropism for beta cells and produced diabetes and the other that did not have a tropism for beta cells and was nondiabetogenic (5).The present investigation was initiated to see, first, whether our stock pool of the M variant of EMC virus was made up of a mixture of diabetogenic and nondiabetogenic virus and, second, whether the nondiabetogenic virus inhibited the development of diabetes. Materials and MethodsMice. Unless otherwise indicated, SJL/J male mice, 5-6 wk old, obtained from The Jackson Laboratory, Bar Harbor, Maine, were used in all experiments. Animals were inoculated with virus by the intraperitoneal route.Pancreatic Beta Cell Cultures. Pancreata were aseptically removed from suckling SJL/J mice, and beta cell cultures were prepared as described previously (9). The cultures were refed at 2-d intervals, and at 6 d the monolayers were used to passage virus. Staining of the monolayers with fluorescein isothiocyanate-labeled antibody to insulin indicated that 40-70% of the cells were beta cells (9).Virus. The M variant of EMC virus (1), prepared as described elsewhere, was passaged five J Abbrev.iations used in this paper: EMC, encephalomyocarditis; FITC, fluorescein isothiocyanate; IRI, immunoreactive insulin; PFU, plaque-forming units; SME, secondary mouse embryo; VSV, vesicular stomatitis virus.

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Reovirus type 3, passaged in pancreatic beta-cell cultures, produced an insulitis when inoculated into 1- to 2-week-old mice. By means of a double-label antibody technique, in which we used fluorescein-labeled antibody to reovirus and rhodamine-labeled antibody to insulin, reovirus antigens were found in beta cells. By electron microscopy, viral particles in different stages of morphogenesis were observed in insulin-containing beta cells but not glucagon-containing alpha cells. The infection resulted in destruction of beta cells, reduction in the insulin content of the pancreas, and alteration in the host's capacity to respond normally to a glucose tolerance test.

Crosstalk of signaling pathways play crucial roles in cell proliferation, cell differentiation, and cell fate determination for development. In the case of ventx1.1 in Xenopus embryos, both BMP-4/Smad-1 and FGF/Xbra signaling induce the expression of neural repressor ventx1.1. However, the details of how these two pathways interact and lead to neural inhibition by ventx1.1 remain largely unknown. In the present study, Xbra directly bound to the ventx1.1 promoter region and inhibited neurogenesis in a Ventx1.1-dependent manner. Furthermore, Smad-1 and Xbra physically interacted and regulated ventx1.1 transcription in a synergistic fashion. Xbra and Smad-1 interaction cooperatively enhanced the binding of an interacting partner within the ventx1.1 promoter and maximum cooperation was achieved in presence of intact DNA binding sites for both Smad-1 and Xbra. Collectively, BMP-4/Smad-1 and FGF/Xbra signal crosstalk cooperate to activate the transcription of neural repressor ventx1.1 in Xenopus embryos. This suggests that the crosstalk between BMP-4 and FGF signaling negatively regulates early neurogenesis by synergistic activation of ventx1.1 in Xenopus embryos.