Biology subjects

Osborn, D. P. S.

Publications and source records attributed to Osborn, D. P. S..

2 recordsLinked to original sources

bioRxiv2019

Fgf-driven Tbx protein activities directly induce myf5 and myod to initiate zebrafish myogenesis

Skeletal muscle derives from dorsal mesoderm that is formed during vertebrate gastrulation. Fibroblast growth factor (Fgf) signalling is known to cooperate with transcription factors of the Tbx family to promote dorsal mesoderm formation, but the role of these proteins in skeletal myogenesis has been unclear. Using the zebrafish, we show that dorsally-derived Fgf signals act through Tbx16 and Tbxta to induce two populations of slow and fast trunk muscle precursors at distinct dorsoventral positions. Tbx16 binds to and directly activates the myf5 and myod genes that are required for commitment to skeletal myogenesis. Tbx16 activity depends on Fgf signalling from the organiser. In contrast, Tbxta is not required for myf5 expression. However, Tbxta binds to a specific site upstream of myod not bound by Tbx16, driving myod expression in the adaxial slow precursors dependent upon Fgf signals, thereby initiating muscle differentiation in the trunk. After gastrulation, when similar muscle cell populations in the post-anal tail are generated from the tailbud, declining Fgf signalling is less effective at initiating adaxial myogenesis, which is instead initiated by Hedgehog signalling from the notochord. Our findings provide insight into the ancestral vertebrate trunk myogenic pattern and how it was co-opted during tail evolution to generate similar muscle by new mechanisms.

developmental biology↗

bioRxiv2017

A mutation in the LMOD1 actin-binding domain segregating with disease in a large British family with thoracic aortic aneurysms and dissections

We describe a mutation in LMOD1, which predisposes individuals to thoracic aortic aneurysms and dissections in a large multi-generation British family. Exome variant profiles for the proband and two distantly related affected relatives were generated and a rare protein-altering, heterozygous variant was identified, present in all the exome-sequenced affected individuals. The allele c.1784T>C, p.(V595A) in LMOD1 is located in a known actin-binding WH2 domain and is carried by all living affected individuals in the family. LMOD1 was further assessed in a consecutive series of 98 UK TAAD patients and one further mutation was found, yielding an incidence of [~]2% in our study group. Assessment of LMOD1 in international TAAD cohorts discovered nine other missense variants of which three were classed as likely pathogenic.\n\nValidation of LMOD1 was undertaken using a zebrafish animal model. Knock-down of both lmod1a and lmod1b paralogs using morpholino oligonucleotides showed a reproducible abnormal phenotype involving the aortic arches under off-target controls. Injection of the human LMOD1 c.1784T>C, p.(V595A) mutation demonstrated a likely dominant negative effect and illustrated a loss of function cause.\n\nMutations found in the WH2 actin-binding domain of LMOD1 may delay actin polymerization and therefore compromise actin length, dynamics and interaction with myosin in the smooth muscle contraction pathway.

genetics↗