Hedgehog pathway modulation by glypican 3-conjugated heparan sulfate.

Glypicans are a family of cell surface heparan sulfate proteoglycans that play critical roles in multiple cell signaling pathways. Glypicans consist of a globular core, an unstructured stalk modified with sulfated glycosaminoglycan chains, and a glycosylphosphatidylinositol anchor. Though these structural features are conserved, their individual contribution to glypican function remains obscure. Here, we investigate how glypican 3 (GPC3), which is mutated in Simpson-Golabi-Behmel tissue overgrowth syndrome, regulates Hedgehog signaling. We find that GPC3 is necessary for the Hedgehog response, surprisingly controlling a downstream signal transduction step. Purified GPC3 ectodomain rescues signaling when artificially recruited to the surface of GPC3-deficient cells but has dominant-negative activity when unattached. Strikingly, the purified stalk, modified with heparan sulfate but not chondroitin sulfate, is necessary and sufficient for activity. Our results demonstrate a novel function for GPC3-associated heparan sulfate and provide a framework for the functional dissection of glycosaminoglycans by in vivo biochemical complementation. This article has an associated First Person interview with the first author of the paper.

Prospects for Precision Medicine in Glomerulonephritis Treatment.

BACKGROUND: Glomerulonephritis (GN) consists of a group of kidney diseases that are categorized based on shared histopathological features. The current classifications for GN make it difficult to distinguish the individual variability in presentation, disease progression, and response to treatment. GN is a significant cause of end-stage renal disease (ESRD), and improved therapies are desperately needed because current immunosuppressive therapies sometimes lack efficacy and can lead to significant toxicities. In recent years, the combination of high-throughput genetic approaches and technological advances has identified important regulators contributing to GN. OBJECTIVES: In this review, we summarize recent findings in podocyte biology and advances in experimental approaches that have opened the possibility of precision medicine in GN treatment. We provide an integrative basic science and clinical overview of new developments in GN research and the discovery of potential candidates for targeted therapies in GN. FINDINGS: Advances in podocyte biology have identified many candidates for therapeutic targets and potential biomarkers of glomerular disease. The goal of precision medicine in GN is now being pursued with recent technological improvements in genetics, accessibility of biologic and clinical information with tissue biobanks, high-throughput analysis of large-scale data sets, and new human model systems such as kidney organoids. CONCLUSION: With advances in data collection, technologies, and experimental model systems, we now have vast tools available to pursue precision medicine in GN. We anticipate a growing number of studies integrating data from high-throughput analysis with the development of diagnostic tools and targeted therapies for GN in the near future.

CONTEXTE: La glomérulonéphrite (GN) consiste en un groupe de troubles rénaux classés en fonction de caractéristiques histopathologiques communes. La classification actuelle de la GN illustre mal la variabilité individuelle dans la présentation, la progression de la maladie et la réponse au traitement. La GN est une cause importante d'évolution vers l'insuffisance rénale terminale (IRT). L'amélioration des traitements est absolument nécessaire, car les thérapies immunosuppressives actuelles manquent parfois d'efficacité et présentent une toxicité élevée. Dans les dernières années, la combinaison d'approches génétiques à haut débit aux avancées technologiques a permis d'identifier des régulateurs importants contribuant à la GN. OBJECTIFS: Cette revue constitue une synthèse des plus récentes découvertes en biologie des podocytes, de même que des avancées dans les approches expérimentales ayant ouvert la voie à la médecine de précision pour le traitement de la GN. L'étude donne un aperçu global des plus récents développements de la recherche sur la GN et discute de la découverte de possibles candidats pour l'élaboration de thérapies ciblées. RÉSULTATS: Les avancées en biologie des podocytes ont permis d'identifier plusieurs candidats de cibles thérapeutiques et de possibles biomarqueurs des troubles glomérulaires. L'objectif de la médecine de précision pour la GN est poursuivi par la contribution des récents progrès technologiques en génétique, par l'accessibilité aux renseignements biologiques et cliniques obtenus grâce aux biobanques, par l'analyse à haut débit de grands volumes de données, et par l'entremise de nouveaux modèles humains tels que les organoïdes rénaux. CONCLUSION: Forts des avancées en collecte de données, en technologie et dans les modèles expérimentaux, nous disposons désormais de plusieurs outils pour approfondir l'apport de la médecine de précision dans le traitement de la GN. Nous prévoyons, dans un avenir rapproché, qu'un nombre grandissant d'études intègreront les données provenant d'analyses à haut débit dans l'élaboration d'outils diagnostiques et de thérapies ciblées pour le traitement de la GN.

Ptch2 shares overlapping functions with Ptch1 in Smo regulation and limb development.

Ptch1 and Ptch2 are highly conserved vertebrate homologs of Drosophila ptc, the receptor of the Hedgehog (Hh) signaling pathway. The vertebrate Ptch1 gene encodes a potent tumor suppressor and is well established for its role in embryonic development. In contrast, Ptch2 is poorly characterized and dispensable for embryogenesis. In flies and mice, ptc/Ptch1 controls Hh signaling through the regulation of Smoothened (Smo). In addition, Hh pathway activation also up-regulates ptc/Ptch1 expression to restrict the diffusion of the ligand. Recent studies have implicated Ptch2 in this ligand dependent antagonism, however whether Ptch2 encodes a functional Shh receptor remains unclear. In this report, we demonstrate that Ptch2 is a functional Shh receptor, which regulates Smo localization and activity in vitro. We also show that Ptch1 and Ptch2 are co-expressed in the developing mouse limb bud and loss of Ptch2 exacerbates the outgrowth defect in the limb-specific Ptch1 knockout mutants, demonstrating that Ptch1 and Ptch2 co-operate in regulating cellular responses to Shh in vivo.