Encephalization, Loading and Bone Formation along the Cranial Vault and Base: Mechanistic Analysis of Basicranial Flexion

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Encephalization, the evolutionary expansion of relative brain size, is a hallmark of Primates and most notable in the amazingly large human brain. While it is evident that primate crania (skulls) have evolved to accommodate larger brain sizes, the mechanistic underpinnings of these modifications are not fully understood. In this project, the investigators will test long-held assumptions about the mechanical role of brain growth on cranial morphology (shape). Using a novel tissue engineering approach to simulate static tensile loads during brain expansion, the osteogenic (bone producing) potential of calvarial, basicranial and mandibular non-sutural bone cells will be examined in a murine model. The research will advance knowledge about the developmental and cellular underpinnings of cranial morphology, provide comparative mammalian data that will inform studies in primate and hominin evolution, and potentially inform clinical research in regenerative medicine. The project will foster interdisciplinary approaches to research and education involving members of under-represented groups in STEM. It will benefit a postdoctoral fellow, graduate students and undergraduates as well as STEM teachers and students, all of whom will participate in presentations and outreach at public and local institutions. Due to its location at the interface of neural and facial skulls, elevated flexion of the mammalian cranial base is depicted as the mechanical consequence of an increasingly globular brain. However, most experimental evidence indicates that calvarial bony tissues are largely buffered against variation in mechanical stimuli. In contrast, the dura mater is known to be affected by tensile forces during brain expansion and induces growth of overlying sutural bone. Surprisingly, there is little evidence about the extent to which neural forces and pro-osteogenic signaling by the dura affect the development of non-sutural bone in the cranial base and vault. A major goal of this project is to detail site-specific and age-related variation in the osteogenic potential and mechanosensitivity of connective tissues in the growing skull, using the responses of mandibular bone cells as a baseline to evaluate calvarial and basicranial cells. The investigators will assess if bone formation in the cranial vault and base is affected by pro-osteogenic signaling in the underlying dura mater. This research is transformative in its integrative perspective and novel use of tissue engineering methods. Experimental data on how the dura mater modulates bone formation in the skull is key for understanding important questions, including the adaptive nature of cranial vault thickness and circumorbital form in primates. The presence of site-specific variation in craniomandibular mechanosensitivity would also emphasize that variation in intrinsic mechanisms of bone formation should be incorporated into future work on hard-tissue adaptations in diverse mammals, including cranial and limb elements with more marked bony responses. The project outcomes will therefore contribute to both theoretical and analytical advances in biological anthropology, organismal biology, mechanobiology and pathobiology. This research is jointly supported by the NSF Biological Anthropology and the Physiological Mechanisms and Biomechanics programs.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.