Biology subjects

Doro, D.

Publications and source records attributed to Doro, D..

4 recordsLinked to original sources

bioRxiv2023

The role of embryonic origins and suture proximity in repair of cranial bone

The cranial sutures are proposed to be a stem cell niche, harbouring skeletal stem cells (SSCs) that are directly involved in development, homeostasis, and healing. Like the craniofacial bones, the sutures are formed from both mesoderm and neural crest. During cranial repair, neural crest cells have been proposed to be key players; however, neural crest contributions to the sutures are not well defined, and the relative importance of suture proximity is unclear. Here, we combine calvarial wounding experiments with genetically labelled mouse models to demonstrate that suture proximity predicts the efficiency of cranial repair. Furthermore, we define the neural crest-mesoderm boundary within the sutures and demonstrate that Gli1+ and Axin2+ SSCs are present in all calvarial sutures examined. We propose that the position of the defect determines the availability of neural crest-derived progenitors, which appear to be a key element in the repair of calvarial defects. Summary statementThis study provides a new examination of the embryonic origins of cranial sutures in mouse. Using genetic lineage labelling, we identify specific contributions of neural crest cells and associated skeletal stem cells during repair of calvarial wounds. This is extremely relevant considering recent findings regarding the role of suture-residing stem cells.

developmental biology↗

bioRxiv2021

Neutralizing antibody-independent immunity to SARS-CoV-2 in hamsters and hACE-2 transgenic mice immunized with a RBD/Nucleocapsid fusion protein

The nucleocapsid (N) and the receptor binding domain (RBD) of the Spike (S) proteins elicit robust antibody and T cell responses either in vaccinated or COVID-19 convalescent individuals. We generated a chimeric protein that comprises the sequences of RBD from S and N antigens (SpiN). SpiN was highly immunogenic and elicited a strong IFN{gamma} response from T cells and high levels of antibodies to the inactivated virus, but no neutralizing antibodies. Importantly, hamsters and the human Angiotensin Convertase Enzyme-2-transgenic mice immunized with SpiN were highly resistant to challenge with the wild type SARS-CoV-2, as indicated by viral load, clinical outcome, lung inflammation and lethality. Thus, the N protein should be considered to induce T-cell-based immunity to improve SARS-CoV-2 vaccines, and eventually to circumvent the immune scape by variants.

immunology↗

bioRxiv2018

The osteogenic potential of the neural crest lineage may contribute to craniosynostosis

The craniofacial skeleton is formed from the neural crest and mesodermal lineages, both of which contribute mesenchymal precursors during formation of the skull bones. The large majority of cranial sutures also include a proportion of neural crest derived mesenchyme. While some studies have addressed the relative healing abilities of neural crest and mesodermal bone, relatively little attention has been paid to differences in intrinsic osteogenic potential. Here we use mouse models to compare neural crest osteoblasts (from frontal bones or dura mater) to mesodermal osteoblasts (from parietal bones). Using in vitro culture approaches we find that neural crest-derived osteoblasts readily generate bony nodules while mesodermal osteoblasts do so less efficiently. Furthermore, we find that co-culture of neural crest-derived osteoblasts with mesodermal osteoblasts is sufficient to nucleate ossification centres. All together, this suggests that the intrinsic osteogenic abilities of neural crest-derived mesenchyme may be a primary driver behind craniosynostosis.

developmental biology↗

bioRxiv2018

GSK3 Controls Migration of the Neural Crest Lineage

Migration of the neural crest lineage is critical to its physiological function. Mechanisms controlling neural crest migration are comparatively unknown, due to difficulties accessing this cell population in vivo. Here, we uncover novel requirements of glycogen synthase kinase 3 (GSK3) in regulating the neural crest. We demonstrate that GSK3 is tyrosine phosphorylated (pY) in neural crest cells and that this activation depends on anaplastic lymphoma kinase (ALK), a protein associated with neuroblastoma. Consistent with this, neuroblastoma cells with pathologically increased ALK activity express high levels of pY-GSK3 and migration of these cells can be inhibited by GSK3 or ALK blockade. In normal neural crest cells, loss of GSK3 leads to increased pFAK and misregulation of Rac1 and lamellipodin, key regulators of cell migration. Genetic reduction of GSK-3 results in failure of migration. All together, this work identifies a role for GSK3 in cell migration during neural crest development and cancer.

developmental biology↗