Proteolytic Processing as a Regulator of BMP-type Signaling in Drosophila Development
Year: 2013
Type: dissertation
Abstract: A small set of highly conserved signaling molecules performs a great number of tasks in different animals and developmental contexts. Among them, the bone morphogenetic proteins (BMPs) constitute a group of growth and differentiation factors that are involved in numerous developmental processes affecting cell proliferation, apoptosis and differentiation. In the fruit fly, Drosophila melanogaster, three BMP type proteins have been identified, each of which has a homolog in mammals. Decapentaplegic (Dpp) is a BMP2/4 type protein which plays a major role in dorsal-ventral patterning of the early embryo. It participates in midgut development, patterning and growth of imaginal tissues, wing vein formation and maintenance of germline stem cells in the germarium. Dpp is a morphogen which requires a second BMP type protein, Screw (Scw) or Glass bottom boat (Gbb) to be able to form proper concentration gradients in developing tissues. Scw and Gbb belong to the BMP5/6/7/8 subfamily and their expression domains are different; Scw is specifically expressed during the early events of embryogenesis, while Gbb has more functional roles during later stages of fly development, like wing morphogenesis. BMP type proteins are produced as large proproteins that require proteolytic cleavage prior to secretion and extracellular gradient formation. This study concentrated on the cleavage of Dpp and Scw to reveal the meaning of post-translational modifications in concentration gradient formation and BMP signaling. Three furin recognition sites were identified in the Dpp proprotein. Mutational analyses indicate that the upstream optimal furin site of the prodomain (furin site (FS) II) is critical for producing ligands and creating a long range concentration gradient in a wing imaginal disc. Cleavage of the other two FSs produce the differently sized Dpp ligands that contribute to BMP gradient formation in the early embryo and wing imaginal disc. It was noted that the cleavage requirements of BMP2/4 type proteins in different species vary to establish species-specific regulation of BMP signaling. Discovery of the scwE1 allele, that causes dominant negative effect in embryos heterozygous for a hypomorphic dpp allele, gave more information about how the cleavage patterns of prodomains can contribute to creating diversity in the regulation of signaling. The mutation responsible for the dominant negative function in scwE1 was located in the cleavage site that is in the prodomain of Scw. Mutational analyses showed that the mature ligand of ScwE1 is produced in lower amounts and in complex with an N-terminal prodomain peptide. ScwE1 preferentially binds Dpp and disrupts normal gradient formation possibly through interactions with molecules within the extracellular matrix. Phylogenetic analyses and functional studies of BMP cleavage mutants propose a mechanism by which post-translational regulation of proproteins modulates BMP signaling.
Source: Työväentutkimus Vuosikirja
Author: Jaana Künnapuu-Vulli
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1558089270