Phenotypic and Biomechanical Effects of Altered Cell Proliferation and Differentiation in the Mouse Skull

长期以来，研究人员一直对哺乳动物头骨进化的关键过程感兴趣。在这里，我们提出了一种独特的方法，将进化发育生物学与功能形态学相结合，以增加我们对哺乳动物头骨进化过程的日益加深的理解。具体来说，我们的总体目标是确定颅骨内的细胞增殖和分化（P&D）如何影响颅骨形状和形状变化，以及这些形态学变化如何影响颅骨功能（通过应变分布测量）。

The search for key processes that underlie the evolution of the mammalian skull has long fascinated researchers. Here, we propose a unique approach that blends evolutionary developmental biology with functional morphology to add to our growing understanding of the processes underlying mammalian skull evolution. Specifically, our overarching goal is to determine how cellular proliferation and differentiation (P&D) within the skull affects skull shape and shape variation and how these changes in morphology impact skull function as measured by strain distribution. Our approach involves three mouse models in which proliferation and differentiation are altered globally, in chondrocytes only and in osteoblasts only. These mouse models allow us to systematically quantify and compare the cell-type specific phenotypic and biomechanical effects of altered P&D. We address our overarching goal through three Aims. Aim 1: To quantify P&D throughout the skull and compare these results among mouse models and throughout development. Results from Aim 1 will provide the first comprehensive look at the patterns of P&D of osteoblasts and chondrocytes throughout all regions of the skull and throughout development. Our findings will provide fundamental information on the role of P&D during normal mouse skull development and they will also inform the cellular mechanism for results of Aims 2 and 3. Aim 2: To determine the effects of altered P&D on skull morphology and phenotypic variation and to determine if these effects are cell-type specific. This Aim will provide insight into how P&D might impact skull evolution through their effects on skull shape and shape variation. We will be able to determine if the phenotypic effects of P&D are diffuse or are localized to specific regions. Results of this Aim will be combined with those of Aims 1 and 3 as a means to integrate phenotypic variation with development and function. Aim 3: To determine the effects of altered P&D on the biomechanical properties of the skull and to determine if these effects are cell-type specific. We will develop the first mouse skull FEM and first set of FEMs to track skull development. These models will allow us to compare approximated biomechanical properties such as stress and strain among mouse models and age groups. We will be able to see how specific variations in skull shape alter biomechanical function, linking variational properties that determine the evolutionary potential of the skull with measures of functional performance. The profound impact of the proposed work stems from the integration of analyses at the cellular, morphological and functional levels. Such integration provides a novel and powerful approach to the study of how generic processes such as P&D could influence the evolutionary potential of the skull through their impact on form and function throughout development.