Role of BCL11B in development of the craniofacial skeleton

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Craniosynostosis, the premature ossification of cranial sutures, is the most clinically important developmental disorder of the skull vault, occurring in ~ 1 in 2,250 live births. Sequelae of this disorder include restricted skull expansion, midfacial hypoplasia, increased intracranial pressure, and craniofacial dysmorphologies, all of which negatively impact respiration, sensory systems, and cognition. Cranial sutures are fibrocellular structures that separate the rigid plates of the skull bones and limit skull deformation due to both tensile and compressive forces. Maintenance of sutural patency is essential to match skull expansion with the explosive increase in brain size of infants—up to 2.4 mm per week during the first year of life. Little is known of the mechanisms underlying preservation of the patent state of cranial sutures— and it is the failure of these mechanisms that results in craniosynostosis. A genetic basis for craniosynostoses is known in only about 25% of patients but the mechanisms by which these mutations result in premature sutural ossification are incompletely understood. A molecular and mechanistic understanding of sutural patency will facilitate development of new avenues to diagnose patients and create patient-specific treatments, which will improve quality of life for craniosynostosis patients. Surgical intervention to create a more normal head shape with increased intracranial volume and reduced intracranial pressure has been the mainstay of craniosynostosis treatment for over a century The objective of this proposal is to identify mechanism(s) and gene networks underlying the maintenance of sutural patency by the transcriptional regulatory protein BCL11B. Our central hypothesis is that BCL11B maintains osteoprogenitors in the sutural mesenchyme at an immature stage and does so by regulating expression of a network of genes that suppresses the osteogenic differentiation program. We will test this hypothesis by achieving two specific aims. In the first Aim we will exploit our in vitro model to determine how osteogenic differentiation is tied to BCL11B expression levels. In the second Aim we will determine the gene network regulated BCL11B in the sutural mesenchyme of calvarial sutures. Our novel mouse models will facilitate identification of gene regulatory networks through which BCL11B controls sutural patency, and guide development of new strategies that couple molecular genetic analyses with primary diagnostic classification of craniosynostosis. This knowledge will improve quality of life for patients with the disease through improved diagnostics, enhanced genetic counselling, and creation of patient-specific treatments. We have documented expertise in mentoring students at all levels. The cutting- edge techniques described in this proposal will provide outstanding training opportunities for undergraduate, professional, and graduate students.