Discovering novel molecular genetic mechanisms that integrate morphogenesis and cell fate determination during vertebrate embryonic development

在脊椎动物胚胎发生过程中，一个不起眼的细胞球迅速增殖，生长，并积极重新塑造成一个可识别的“成人”身体计划。这种非凡的转变涉及细胞形状、模式和运动的无数变化，最终组装成复杂的结构，如颅骨骼（颌骨和头骨）。这些事件中的任何一个轻微的变化都可以戏剧性地改变正常形态。 我的实验室致力于发现控制颅骨骼模式和形态发生的新的分子和遗传机制。为此，我们进行了一项合作和跨学科的研究，以确定纯种狗品种之间观察到的极端颅面多样性的遗传基础（这是复杂发育性状遗传研究的理想选择）。我们的工作确定了许多令人兴奋的新基因，这些基因被预测可以调节颅面发育-然而，它们的实际活动仍然未知。 在下面的建议中，我们使用一个优雅的实验模型系统-斑马鱼-来研究候选基因的功能。斑马鱼的胚胎发育与哺乳动物非常相似。然而，斑马鱼胚胎是丰富的，透明的，容易在显微镜下生长，我们已经建立了强大的技术，实际成像（在真实的时间）在颅面发育过程中发生的细胞结构和运动的微观变化。此外，斑马鱼非常适合遗传研究，我们可以选择性地和系统地“敲低”基因功能，以研究其对胚胎发育的影响。 在这里，我们采用细胞生物学，胚胎学和经典的遗传学方法在斑马鱼，以确定我们新发现的候选基因如何控制胚胎图案和形态发生。拟议的研究具有巨大的潜力，以扩大我们的理解颅面发育，并确定新的分子和细胞生物学机制，协调外在的图案线索与细胞命运的决定和细胞运动在脊椎动物胚胎发育。

During vertebrate embryogenesis, an unassuming ball of cells rapidly proliferates, grows, and is actively re-modeled into a recognizable 'adult' body plan. This remarkable transformation involves countless changes in cell shape, pattern and movement, which ultimately assemble complex structures like the cranioskeleton (jaws and skull). Slight changes to any of these events can dramatically alter normal form. My lab seeks to discover novel molecular and genetic mechanisms that control cranioskeletal patterning and morphogenesis. To this end, we undertook a collaborative and cross-disciplinary study to determine the genetic basis of extreme craniofacial diversity observed between purebred dog breeds (which are ideal for genetic studies of complex developmental traits). Our work identified many exciting new genes that are predicted to regulate craniofacial development - however, their actual activities remain unknown. In the following proposal, we use an elegant experimental model system - the zebrafish - to investigate candidate gene function. Zebrafish embryonic development is remarkably similar to that of mammals. However, zebrafish embryos are abundant, transparent, easily grown under a microscope, and we have established powerful techniques to actually image (in real time) the microscopic changes in cell structure and movement that occur during craniofacial development. Furthermore, zebrafish are well suited for genetic studies, and we can selectively and systematically "knockdown" gene function to study its effect on embryogenesis. Here, we employ cell biology, embryology, and classic genetic approaches in zebrafish to determine how our newly identified candidate genes control embryonic patterning and morphogenesis. Proposed research holds tremendous potential to expand our understanding of craniofacial development, and to identify novel molecular and cell biological mechanisms that co-ordinate extrinsic patterning cues with cell fate determination and cell movement during vertebrate embryonic development.