We travelled to Lund this month to see Anders Aspberg and discuss potential publications and future collaboration with him and his lab. I gave a presentation on our Xbp1 research to the faculty, and we discussed projects and ideas over a very productive couple of days. Lots of exciting data, watch this space!
Early Bird registration and Abstract submission deadline is on 8th February 2019 (£80 students, £100 members or £130 non-members; late registration: £100 students, £120 members, non-member £150). For more details, please login to bsmb.ac.uk or mbi.ie
Pigs in blankets and Secret Santa 🙂
Bell PA, Dennis EP, Hartley CL, Jackson RM, Porter A, Boot-Handford RP, Pirog KA, Briggs MD.
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) resident protein that can be secreted due to an imperfect KDEL motif. MANF plays a cytoprotective role in several soft tissues and is upregulated in conditions resulting from intracellular retention of mutant protein, including two skeletal diseases, metaphyseal chondrodysplasia type Schmid (MCDS) and multiple epiphyseal dysplasia (MED).
The role of MANF in skeletal tissue homeostasis is currently unknown. Interestingly, cartilage-specific deletion of Manf in a mouse model of MED resulted in increased disease severity, suggesting its upregulation may be chondroprotective. Treatment of MED chondrocytes with exogenous MANF led to a decrease in the cellular levels of BiP (GRP78), confirming MANF’s potential to modulate ER stress responses. However, it did not alleviate the intracellular retention of mutant matrilin-3, suggesting that it is the intracellular MANF that is of importance in the pathobiology of skeletal dysplasias.
The Col2Cre-driven deletion of Manf from mouse cartilage resulted in a chondrodysplasia-like phenotype. Interestingly, ablation of MANF in cartilage did not have extracellular consequences, but led to an upregulation of several ER-resident chaperones including BiP. This apparent induction of ER-stress in turn led to dysregulated chondrocyte apoptosis and decreased proliferation, resulting in reduced long bone growth.
We have previously shown that ER stress is an underlying disease mechanism for several skeletal dysplasias. The cartilage-specific deletion of Manf described in this study phenocopies our previously published chondrodysplasia models, further confirming that ER-stress itself is sufficient to disrupt skeletal growth and thus represents a potential therapeutic target.
Desbuquois dysplasia type 1 (DBQD1) is a chondrodysplasia caused by mutations in CANT1 gene encoding an ER/Golgi calcium activated nucleotidase 1 that hydrolyses UDP. Here, using Cant1 knock-in and knock-out mice recapitulating DBQD1 phenotype, we report that CANT1 plays a crucial role in cartilage proteoglycan synthesis and in endochondral ossification. Specifically, the glycosaminoglycan synthesis was decreased in chondrocytes from Cant1 knock-out mice and their hydrodynamic size was reduced, whilst the sulfation was increased and the overall proteoglycan secretion was delayed. Interestingly, knock-out chondrocytes had dilated ER cisternae suggesting delayed protein secretion and cellular stress; however, no canonical ER stress response was detected using microarray analysis, Xbp1 splicing and protein levels of BiP and ATF4. The observed proteoglycan defects caused deregulated chondrocyte proliferation and maturation in the growth plate resulting in the reduced skeletal growth. In conclusion, the pathogenic mechanism of DBQD1 comprises deregulated chondrocyte performance due to defective intracellular proteoglycan synthesis and altered proteoglycan properties in the extracellular matrix.
We’re back from our 3rd Biannual International ECM and ER Stress Meeting in autumnal Allendale full of great memories and collaborative ideas. Thank you all for coming and sharing your work. Best science is done with friends!
Beth defended her PhD thesis on investigation of the pathomolecular mechanism of two aggrecan mutations leading to OCD and SEMD using mouse models of disease.
Thank you to Prof Frank Zaucke from Frankfurt and Dr Andy Knight from Newcastle University for examining the thesis and well done Beth, all the best in your future career!
Dame Allan’s Schools holds a biennial Higher Education & Careers Convention and invire presenters, employers, and universities to inspire and inform their students as they make plans for their future. We’ll be there on the 4th of October, chatting about genetic research and academic life and inspiring the young minds. We’ll show some cool science too!
Identification of the Human Skeletal Stem Cell
Charles K.F. Chan, Gunsagar S. Gulati, Rahul Sinha, Justin Vincent Tompkins, Michael Lopez, Ava C. Carter, Ryan C. Ransom, Andreas Reinisch, Taylor Wearda, Matthew Murphy, Rachel E. Brewer, Lauren S. Koepke, Owen Marecic, Anoop Manjunath, Eun Young Seo, Tripp Leavitt, Wan-Jin Lu, Allison Nguyen, Stephanie D. Conley, Ankit Salhotra, Thomas H. Ambrosi, Mimi R. Borrelli, Taylor Siebel, Karen Chan, Katharina Schallmoser, Jun Seita, Debashis Sahoo, Henry Goodnough, Julius Bishop, Michael Gardner, Ravindra Majeti, Derrick C. Wan, Stuart Goodman, Irving L. Weissman, Howard Y. Chang, Michael T. Longaker
Cell 2018; 175 (1), 43-56.e21 DOI: 10.1016/j.cell.2018.07.029
A lovely walk, great chilli and a fire, what’s not to like? 🙂
And a big welcome to Helen Dietmar, a new PhD student in Prof Mike Briggs’s lab!
