title: Expression of the heparin-binding cytokines, midkine (MK) and HB-GAM (pleiotrophin) is associated with epithelial-mesenchymal interactions during fetal development and organogenesis.
abstract: Midkine (MK) and heparin binding-growth associated molecule (HB-GAM or pleiotrophin), constitute a new family of heparin-binding proteins implicated in the regulation of growth and differentiation (T. Muramatsu (1993) Int. J. Dev. Biol. 37, 183-188). We used affinity-purified antibodies against MK and HB-GAM to analyze their distribution during mouse embryonic development. From 9 to 14.5 day post-coitum (dpc), both proteins were detected in central and peripheral nervous systems, facial processes, limb buds, sense organs, respiratory, digestive, urogenital, and skeletal systems. MK and HB-GAM were often localized on the surface of differentiating cells and in basement membranes of organs undergoing epithelial-mesenchymal interactions. The level of MK protein decreased considerably in the 16.5 dpc embryo, whereas HB-GAM staining persisted in many tissues. Our in situ hybridization results revealed a widespread expression of MK transcripts that was not always consistent with the distribution of MK protein in developing tissues. In many epithelio-mesenchymal organs MK and HB-GAM were codistributed with syndecan-1, a cell surface proteoglycan. In limb buds and facial processes, MK, HB-GAM, and syndecan-1 were localized to the apical epithelium and the adjacent proliferating mesenchyme. Both MK and HB-GAM bound syndecan-1 in solid-phase assays in a heparan sulfate-dependent manner. The biological effects of MK and HB-GAM on limb and facial mesenchyme were studied in vitro by application of beads preloaded with the proteins. Neither MK nor HB-GAM stimulated mesenchymal cell proliferation or induced syndecan-1 expression. Taken together these results indicate that MK and HB-GAM may play regulatory roles in differentiation and morphogenesis of the vertebrate embryo, particularly in epithelio-mesenchymal organs, and suggest molecular interactions with syndecan-1.
authors.affiliation: Department of Pedodontics and Orthodontics, University of Helsinki, Finland.
authors.forename: T A
authors.initials: TA
authors.lastname: Mitsiadis
authors.forename: M
authors.initials: M
authors.lastname: Salmivirta
authors.forename: T
authors.initials: T
authors.lastname: Muramatsu
authors.forename: H
authors.initials: H
authors.lastname: Muramatsu
authors.forename: H
authors.initials: H
authors.lastname: Rauvala
authors.forename: E
authors.initials: E
authors.lastname: Lehtonen
authors.forename: M
authors.initials: M
authors.lastname: Jalkanen
authors.forename: I
authors.initials: I
authors.lastname: Thesleff
mesh_terms: D000818:Animals; D002319:Cardiovascular System / Q000737:chemistry / Q000196:embryology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005314:Embryonic and Fetal Development / Q000235:genetics / Q000502:physiology*; D004848:Epithelium / Q000737:chemistry; D005121:Extremities; D005145:Face; D006493:Heparin / Q000378:metabolism; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics; D051379:Mice; D000078792:Midkine; D008934:Mitogens / Q000235:genetics / Q000378:metabolism*; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology; D009420:Nervous System / Q000737:chemistry / Q000196:embryology; D011509:Proteoglycans / Q000032:analysis / Q000235:genetics; D053668:Syndecan-1; D053667:Syndecans
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D008562:Membrane Glycoproteins; D008934:Mitogens; D011509:Proteoglycans; C508242:Sdc1 protein, mouse; D053668:Syndecan-1; D053667:Syndecans; C066845:pleiotrophin; D000078792:Midkine; D006493:Heparin