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Title: Exploring the generative architecture of intramembranous ossification
Author: Jordan, Kate Weymouth-Crocker
ISNI:       0000 0004 2725 3534
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2011
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Dermal bone is the oldest of vertebrate hard tissues; despite its evolutionary and developmental significance, its histogenesis is poorly understood. The present thesis investigates aspects of frontal bone and clavicle formation including layer morphogenesis, vasculogenesis, biomineralization and muscle:bone connectivity. I apply an array of molecular markers in a 3D time-course at single-cell resolution to genetically tracked and mutated mouse cell lineages. I uncover a growth mode not commensurate with traditional models of intramembranous ossification, whereby two molecularly distinct generative layers (external and internal) intercalate cells into the intervening cancellous/spongious layer, which elaborates with time. Cells in the external layer organize into rosette formations that act as archetypal units of cellular introgression, bearing the hallmarks of a tangential convergenceextension movement. Both osteoblasts and endothelia enter into the spongious bone from the generative layers, forming an osteoblastendothelial interface in the cancellous layer and de novo vasculature in the maturing bone. Ablation of Hand2 in the neural crest lineage abrogates this internal sheet formation, substantiating the notion of ingression from the outer and inner (Hand2+) layers; Hand2 mediates this process in vivo by regulating the nuclear import of Runx2 protein, at the post-transcriptional level. The highly dynamic processes of layer formation and vascularization are related to bone mineralization using a time-course of matrix labeling, examined ex vivo and in vivo; this reveals extensive remodeling of existing mineral by osteoblasts and endothelial cells, which modulate the collagen scaffolds along which hydroxyapatite crystals are assembled in the absence of osteoclasts. This sheds light on possible mechanisms of skeletogenesis in acellular bone among jawed vertebrate ancestors. I finally investigate endochondral ossification of classically mesodermal occipital regions and find an additional neural crest-based invasion in those tissues. This sheds light onto the etiology of neurocristopathies and prompts a modification of present fate maps.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QP Physiology