Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions converge on a membrane protein complex, the MMM complex, that promotes degradation of the Hh transducer Smoothened (SMO). Deficiency of the MMM component MOSMO results in elevated SMO and increased Hh signaling, causing multiple birth defects. In utero exposure to a teratogen that directly inhibits SMO reduces the penetrance and expressivity of birth defects in Mosmo−/- embryos. Additionally, tissues that develop normally in Mosmo−/- embryos are refractory to the teratogen. Thus, changes in the abundance of the protein target of a teratogen can change birth defect outcomes by quantitative shifts in Hh signaling. Consequently, small molecules that re-calibrate signaling strength could be harnessed to rescue structural birth defects.
Category: Trauma; Ankle Introduction/Purpose: Lower limb fractures account for a third of all orthopaedic injuries of which 22% are ankle fractures. With a gradual move toward minimally invasive surgery for ankle fractures, intramedullary implants have evolved over the years to dedicated fixation devices for fibula fractures. The aim of this study was to determine the clinical outcomes following fibula nail fixation and to identify the indication for the use of fibula nails in ankle fractures. Methods: A retrospective study of adult patients from 2 major trauma centers (MTCs) and 9 trauma units (TUs) who underwent fibula nail fixation for AO/OTA 44 fractures between January 1, 2018, and October 31, 2020 was conducted. Fracture were classified based on the Weber or AO/OTA classification. Operative fixation was performed using the Acumed Fibula Rod (Acumend Fibula Rod System, Hilsboro, OR, USA) and a minimally invasive direct approach to the lateral malleolsus with radiography-guided percutaneous screw insertion was used in all patients. The outcome measures included infection, metalwork complications, nonunion or malunion, time to union, and length of inpatient hospital stay. Results: Ninety-five patients were included, with a mean age of 66 years; 57.9% of patients were female. The average body mass index was 30. Sixty-nine patients (72.6%) sustained a Weber B and 24 (27.4%) sustained a Weber C fracture. In addition, 26.3% were open fractures and all patients had soft tissue compromise affecting the lateral malleolus. The calculated infection rate for fibula nail was 4.2% and metalwork complication rate was 5.2%. The nonunion and malunion rate was 8.4% and rate of removal of hardware was 2.1%. The average time to union was 12.5 weeks, and length of inpatient stay was 9.4 days (SD 10). Conclusion: This is the largest multicenter to date which demonstrates that use of a fibula nail appears to be a safe approach to treating patients who have a physiologically higher risk of surgery, poor skin condition, and a complex fracture pattern. The risks of wound and metalwork complicatons appear relatively low following fibula nail fixation in comparison to ankle ORIF's.
The etiology of congenital heart defects (CHDs), amongst the most common human birth defects, is poorly understood partly because of its complex genetic architecture. Here we show that two genes previously implicated in CHDs, Megf8 and Mgrn1, interact genetically and biochemically to regulate the strength of Hedgehog signaling in target cells. MEGF8, a singlepass transmembrane protein, and MGRN1, a RING superfamily E3 ligase, assemble to form a transmembrane ubiquitin ligase complex that catalyzes the ubiquitination and degradation of the Hedgehog pathway transducer Smoothened. Homozygous Megf8 and Mgrn1 mutations increased Smoothened abundance and elevated sensitivity to Hedgehog ligands. While mice heterozygous for loss-of-function Megf8 or Mgrn1 mutations were normal, double heterozygous embryos exhibited an incompletely penetrant syndrome of CHDs with heterotaxy. Thus, genetic interactions between components of a receptor-like ubiquitin ligase complex that tunes morphogen signaling strength can cause a birth defect syndrome inherited in an oligogenic pattern.and MGRN1 Mut2 were expressed at equivalent levels as MGRN1 ( Fig. 2F) and maintained their stable interaction with MEGF8 ( Fig. S4C), demonstrating their integrity. These results support the conclusion that both the stable interaction of MGRN1 with MEGF8 and its E3 ligase function are required to attenuate Hh signaling. The MEGF8-MGRN1 complex ubiquitinates SMOAt this point our data suggested that MGRN1 functions as a membrane-tethered ubiquitin ligase complex that attenuates Hh signaling by reducing SMO abundance at the cell surface and primary cilium. This mechanism is reminiscent of a prominent membrane-localized ubiquitination system that attenuates WNT signaling by decreasing cell-surface levels of Frizzled (FZD) proteins, receptors for WNT ligands that are the closest relatives of SMO in the GPCR superfamily (Bjarnadóttir et al., 2006). Two transmembrane RING-family E3 ubiquitin ligases, ZNRF3 and RNF43, attenuate WNT responsiveness by directly ubiquitinating FZD and promoting its clearance from the cell surface (Hao et al., 2012;Koo et al., 2012).To examine if a similar ubiquitination system regulates Hh signaling sensitivity, we measured the stability of SMO at the plasma membrane using a non-cell permeable biotinylation reagent that only labels proteins at the cell surface in wild-type, Megf8 -/-, and Mgrn1 -/-;Rnf157 -/cells (Fig. 3A). Both the steady state abundance and the stability of cellsurface SMO were markedly greater in both mutant cell lines compared to wild-type cells ( Figs. 3B and 3C). The increase in ciliary SMO abundance (Fig. 1C) is likely a secondary consequence of elevated SMO at the plasma membrane, because plasma membrane-localized SMO can enter the cilia by a lateral transport pathway (Milenkovic et al., 2009). These results are analogous to how the stability of cell-surface FZD is enhanced when the ligases ZNRF3 or RNF43 are inactivated (Hao et al., 2012;Koo et al., 2012), prompting us to consider whether SMO is a substra...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.