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

长期以来，寻找哺乳动物头骨进化的关键过程一直令研究人员着迷。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，以加深我们对哺乳动物头骨进化过程的理解。具体地说，我们的首要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，以及这些形态变化如何影响通过应变分布衡量的颅骨功能。*我们的方法涉及三个小鼠模型，在这些模型中，增殖和分化被整体改变，仅在软骨细胞中和仅在成骨细胞中。这些小鼠模型使我们能够系统地量化和比较改变的P&D对细胞类型、特定表型和生物力学的影响。我们通过三个目标来解决我们的首要目标。*目标1：量化整个头骨的P&D，并在小鼠模型和整个发育过程中比较这些结果。AIM 1的结果将首次全面观察成骨细胞和软骨细胞在颅骨所有区域和整个发育过程中的P&D模式。我们的发现将为P&D在正常小鼠颅骨发育中的作用提供基本信息，也将为AIMS 2和AIMS 3结果的细胞机制提供信息。目标2：确定P&D改变对头骨形态和表型变异的影响，并确定这些影响是否是细胞类型特异性的。这一目标将提供关于P&D如何通过对头骨形状和形状变化的影响来影响头骨进化的洞察。我们将能够确定P&D的表型效应是弥漫性的还是局限于特定区域的。这一目标的结果将与目标1和目标3的结果相结合，作为一种将表型变化与发育和功能相结合的手段。*目标3：确定P&D改变对颅骨生物力学特性的影响，并确定这些影响是否具有细胞类型特异性。我们将开发第一个小鼠头骨有限元和第一套FEMS来跟踪头骨的发育。这些模型将使我们能够比较小鼠模型和年龄组之间近似的生物力学特性，如应力和应变。我们将能够看到头骨形状的特定变化如何改变生物力学功能，将决定头骨进化潜力的变化特性与功能表现的衡量标准联系起来。*拟议工作的深远影响来自细胞、形态和功能层面的综合分析。这种整合为研究P&D等通用过程如何通过影响整个发育过程中的形态和功能来影响头骨的进化潜力提供了一种新颖而有力的方法。

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.