The greater basicranium during development and aging: Searching for molecular and biomechanical mechanisms underlying human clinicopathologies

This study investigates the development and morphology of the cranial base and neck and its contribution to understanding the basic biological forces that underlie a number of human clinicopathologies including those of the head and neck. These relationships will be examined through the dual lenses of molecular biology and anatomical analysis both during development and in aging. The data suggest that a region of the cranial base defined by the petro-occipital fissure is tightly regulated during development and aging. When perturbed during development or as part of the normal aging process, clinicopathologies may develop. The POF may also provide information about the molecular mechanisms underlying changes to its morphology. The anatomical analysis used in this study included postmortem dissection of human adult/fetal cadaveric material (n=29), and human, rat and mouse skeletal analysis (n=132). In addition, histologic analysis of tissue and radiographic analysis was undertaken to determine morphological changes to the POF and skeleton. Molecular techniques included two screens to identify novel genes that may be involved in the development of the greater basicranium. Tissue was collected from specific regions of the branchial arches and developing hindbrain of stage c17-21 chicken embryos (n=200). In situ hybridization was used to characterize the expression pattern of 55 clones using 110 digoxigenin labeled RNA probes in the developing chicken embryo. Further study of one gene, dorsal neural tube nuclear protein (DNTNP) suggest that it plays a role in the morphology of the greater basicranium. Studies to determine the function of DNTNP and its role in the greater basicranium included in vitro cellular localization studies, in silico analysis, and anatomical studies of a DNTNP knockout mouse. These combined anatomical and molecular data suggest that the POF may act as a sentinel system for human clinicopathologies and may help to identify their underlying biological bases. Human clinicopathologies commonly linked to changes to the cranial base include age related hearing loss, bone metabolism dysfunction, upper respiratory tract dysfunction, malocclusion and certain cranial base chondrosarcomas.