Low-Density Lipoprotein Receptors in Signaling Modulation and Development
Dietrich, Martin Frederik
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The Low-Density Lipoprotein Receptor gene family is a group of ancient membrane receptors. Originally implied in cargo transport and development of atherosclerosis, the number of members and the diversity of functions have been greatly expanded. LRP1, LRP1b and LRP4 are gene family members that are implicated in the regulation of signaling pathways at the intracellular, extracellular and transcriptional level. These regulations confer viability, control the cellular proliferation at several molecular steps, and allow for proper organ formation by moderating and integrating cellular signaling pathways. / The use of knockin mutant mice has, for the first time, implicated the extracellular domains of LRP1b and LRP4 in signaling modulation in development. While the complete knockout of either receptor is embryonically lethal, the expression of a truncated receptor, spanning only the extracellular domain, confers viability and only a mitigated phenotype. / For LRP4, the difference is most visible in the kidney. The present LRP4 extracellular preserves thresholds critical for organogenesis, yet, the complete absence displays a subpenetrant phenotype of kidney agenesis. In this thesis work, results demonstrate the ability of the LRP4 extracellular domain to not only bind a broad variety of soluble ligands in the extracellular space, but further to influence the Wnt, and possibly others, signaling pathways that are required for kidney development. / In an osteoblast-specific model of LRP1 knock-out, the relationship between theLRP1and the PDGF receptor has been further investigated. LRP1 is known to negatively regulate the PDGF receptor. However, the exact mechanism(s) are not fully understood. In the wild-type, PDGF receptor beta binds directly to LRP1 upon ligand stimulation. LRP1 knockout leads to significant upregulation of the PDGF receptor beta at the protein level. The stimulation of the receptor with PDGF-BB, its corresponding ligand, leads to overactivation of the signaling pathway with both increased turnover and phosphorylation/activation of the receptor, demonstrated by cellular proliferation and p21 downregulation. In vivo, the LRP1 knockout leads to a bone-derived hyperproliferation with formation of tumors at the epiphysis. The in vitro experiments are supporting evidence, combined with previously published literature, to imply the LRP1/PDGF receptor pathway.