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A study relating the investigation of transmembrane signaling mechanisms particularly the growth factor activin has resulted in the overexpression, purification and preliminary characterization of the mouse type II activin receptor's extracellular domain. It was demonstrated that this receptor domain is monomeric in solution and is capable of competing with the type II activin receptor. Other results of the study are thoroughly discussed.

We report the isolation and characterization of a new inhibitory Smad in Xenopus, which we have designated as Xenopus Smad7. Smad7 is present at fairly constant levels throughout early development and at blastula stages enriched in the ventral side of the animal hemisphere. The induction of mesoderm by TGF-[Beta]-like signals is mediated by receptor ALK-4 and we show that Smad7 blocks signaling of ALK-4 in a graded fashion: lower levels of Smad7 block activation of dorsal mesoderm genes and higher levels block all mesoderm genes expression. Smad7 is able to directly activate neural markers in explants in the absence of mesoderm or endoderm. This neural-inducing activity of Smad7 may be due to inhibition of BMP-4 signaling because Smad7 can also block BMP-4-mediated mesoderm induction. Thus, Smad7 acts as a potent inhibitor of mesoderm formation and also activates the default neural induction pathway. Key Words: Smads; germ layer; cell fate specification; TGF-[Beta]; ectoderm.

The effects of corticotropin-releasing factor (CRF) and urocortin (Ucn) on cardiac hemodynamics and performance were analyzed in chronically instrumented, conscious sheep. The rate of cardiac contractility, aortic blood flow, mean arterial pressure and cardiac output was altered in a dose-dependent manner by injections of Ucn in conscious sheep. However, the administration of CRF antagonists attenuated the cardiac effects of Ucn. Furthermore, increased cardiac contractility due to Ucn indicated the potent inotropic effects of the compound which regulates peripheral hemodynamics.

Members of the transforming growth factor [Beta] (TGF-[Beta]) superfamily are involved in diverse physiological activities including development, tissue repair, hormone regulation, bone formation, cell growth, and differentiation. At the cellular level, these functions are initiated by the interaction of ligands with specific transmembrane receptors with intrinsic serine/threonine kinase activity. The signaling pathway that links receptor activation to the transcriptional regulation of the target genes is largely unknown. Recent work in Drosophila and Xenopus signaling suggested that Mad (Mothers against dpp) functions downstream of the receptors of the TGF-[Beta] family. Mammalian Mad1 has been reported to respond to bone morphogenetic protein (BMP), but not to TGF-[Beta] or activin. We report here the cloning and functional studies of a novel mammalian Mad molecule, Mad3, as well as a rat Mad1 homologue. Overexpression of Mad3 in a variety of cells stimulated basal transcriptional activity of the TGF-[Beta]/activin-responsive reporter construct, p3TP-Lux. Furthermore, expression of Mad3 could potentiate the TGF-[Beta]- and activin-induced transcriptional stimulation of p3TP-Lux. By contrast, overexpression of Mad1 inhibited the basal as well as the TGF-[Beta]/activin induced p3TP-Lux activity. These findings, therefore, support the hypothesis that Mad3 may serve as a mediator linking TGF-[Beta]/activin receptors to transcriptional regulation.

Urocortin is a mammalian neuropeptide which has sequential identity with fish urotensin I and corticotropin-releasing factor (CRF). The transfected type-1 CRF receptors are activated on coordination with urocortin. Urocortin potentiates the secretion of adrenocorticotropic hormone both in vivo and in vitro. Compared to CRF, urocortin effectively binds to and activates type-2 CRF receptors.

Complete coding regions of activin receptors cActR-IIA and -IIB cDNAs were subcloned to determine whether activin can induce mesoderm in chick embryo despite the absence of the hypoblast. Expression of the receptors was detected in the primitive streak by in situ hybridization, suggesting that these genes had been activated. In vitro assay for differentiation showed that primitive streak responds to activin by differentiating into a variety of mesodermal cell types. These results show that activin activates signaling pathways during various stages of development.

PCR cloning, library screening and RNA blotting procedures reveal a new gene univin, encoding the transformation growth factor beta (TGF-beta) and belonging to the bone morphogenetic protein group in the sea urchin Stronglyocentrotus purpuratus. The cDNA clone of the gene contains a 383-amino acid residue protein with seven cysteine residues and a cluster of basic residues. The spatial and temporal patterns of the gene vary at different developmental stages and are similar to those of SpAN gene, suggesting a correlation between SpAN and univin in regulating developmental stages in sea urchin embryo.