Andrew Nash

DAN is a secreted glycoprotein related to Xenopus cerberus

We report that DAN, a potential cell cycle regulator and tumour suppressor, is a secreted glycoprotein related to Xenopus cerberus. DAN, cerberus, its mouse relative Cer-1/cer-l/Cerberus-like/Cerr1, and the recently described factor DRM/Gremlin, appear to be members of the cystine knot superfamily, which includes TGFbetas and BMPs. Like cerberus and mCer-1, DAN-induced cement glands as well as markers of anterior neural tissue and endoderm in Xenopus animal cap assays, features of BMP signalling blockade. During mouse embryogenesis, Dan was expressed from E8.5 in cranial mesenchyme and somites, then later in limb and facial mesenchyme. The pattern in somites was highly dynamic, with transcripts initially localized to the caudal half of the nascent epithelial somite, then, after maturation, to sclerotomal cells adjacent to the neural tube. Dan was also expressed in the developing myotome. The expression domains include sites in which BMP inhibition is known to be important for development. Thus, DAN appears to be a secreted factor belonging to the cystine knot superfamily, and one of a growing number of antagonists acting to modulate BMP signalling during development.

Suckling defect in mice lacking the soluble haemopoietin receptor NR6

Cytokines control a variety of cellular responses including proliferation, differentiation, survival and functional activation, via binding to specific receptors expressed on the surface of target cells [1]. The cytokine receptors of the haemopoietin family are defined by the presence of a conserved 200 amino acid extracellular domain known as the haemopoietin domain [2]. We report here the isolation of NR6, a haemopoietin receptor that, like the p40 subunit of interleukin-12 (IL-12) [3] and the EBI3 gene induced by Epstein-Barr virus infection in lymphocytes [4], contains a typical haemopoietin domain but lacks transmembrane and cytoplasmic domains. Although in situ hybridisation revealed NR6 expression at multiple sites in the developing embryo, mice lacking NR6 did not display obvious abnormalities and were born in the expected numbers. Neonatal NR6(-/-) mice failed to suckle, however, and died within 24 hours of birth, suggesting that NR6 is necessary for the recognition or processing of pheromonal signals or for the mechanics of suckling itself. In addition, NR6(-/-) mice had reduced numbers of haemopoietic progenitor cells, suggesting a potential role in the regulation of primitive haemopoiesis.

Cytokines: From the laboratory to the clinic

Despite limitations associated with the use of protein‐based drugs, cytokines / growth factors have proven to be valuable therapeutics in the treatment of a variety of chronic and acute disorders. With the ongoing discovery of novel cytokines, and the recognition of new biological activities associated with existing cytokines, the therapeutic utility of these molecules will inevitably expand. In this article, we review three areas of our research activity that represent distinct phases in the therapeutic exploitation of cytokines. First, we discuss progress on the clinical development of leukaemia inhibitory factor (LIF). LIF, a pleiotropic cytokine, has potent neurotrophic effects and a recombinant human version (AM424) is being developed for the treatment of peripheral neuropathies. Second, we describe progress on the characterisation of a novel member of the vascular endothelial growth factor (VEGF) family. Therapeutic angiogenesis is an emerging approach for the treatment of ischaemic heart and limb disease and the cytokines that regulate angiogenesis, such as members of the VEGF family, are the subject of intense interest. Finally, we describe the discovery of a novel class of intracellular proteins (suppressors of cytokine signaling, SOCS) that may play a key role in the downregulation of cytokine signaling. As key regulators of cytokine signaling these molecules represent an exciting new target for drug discovery. Drug Dev. Res. 46:197–205, 1999.