Abstract
Midkine (MDK) and Pleiotrophin (PTN) are small heparin-binding cytokines with closely related structures. The Drosophila genome harbours two genes encoding members of the MDK/PTN family of proteins, known as miple1 and miple2. We have investigated the role of Miple proteins in vivo, in particular with regard to their proposed role as ligands for the Alk receptor tyrosine kinase (RTK). Here we show that Miple proteins are neither required to drive Alk signaling during Drosophila embryogenesis, nor are they essential for development in the fruit fly. Additionally we show that neither MDK nor PTN can activate hALK in vivo when ectopically co-expressed in the fly. In conclusion, our data suggest that Alk is not activated by MDK/PTN related growth factors Miple1 and Miple 2 in vivo.
Highlights
Since their identification the small secreted molecules Midkine (MDK) and Pleiotrophin (PTN) have been implicated in a multitude of developmental events including enhancement of cell growth and survival, cell migration, angiogenesis, neurite outgrowth and development
The related family member PTN known as Heparin-Binding Growth-Associated Molecule (HB-GAM) [6,7,8], Heparin-Binding Neurotrophic Factor or Neurite-promoting Factor (HBNF) [9], Osteoblast Specific Protein-1 (OSF-1) [10] and Heparin Affin Regulatory Peptide (HARP) [11], was first purified from bovine uterus as a weak mitogen towards fibroblasts
We find no in vivo evidence for the activation of Alk signaling in developing visceral mesoderm (VM) by Miple proteins
Summary
Since their identification the small secreted molecules Midkine (MDK) and Pleiotrophin (PTN) have been implicated in a multitude of developmental events including enhancement of cell growth and survival, cell migration, angiogenesis, neurite outgrowth and development (reviewed in [1], and [2]). The related family member PTN known as Heparin-Binding Growth-Associated Molecule (HB-GAM) [6,7,8], Heparin-Binding Neurotrophic Factor or Neurite-promoting Factor (HBNF) [9], Osteoblast Specific Protein-1 (OSF-1) [10] and Heparin Affin Regulatory Peptide (HARP) [11], was first purified from bovine uterus as a weak mitogen towards fibroblasts Given that both MDK and PTN encode small secreted cytokines with heparinbinding properties, they have long been considered to be functional ligands for cell surface receptors. Alk activation by a Jeb-like ligand is functionally conserved in the nematode C. elegans where an Alk homologue is encoded by the scd-2 gene [30,31] and the Jeb homologue hen-1 [32] Together they regulate dauer formation in the worm by modulating TGF-b signaling and its response to dauer pheromone [33]. Our data suggests that neither Miple nor Miple activate the Alk RTK in vivo during Drosophila development
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