Dorsal-Ventral Pattern Formation in the Zebrafish Embryo

描述(申请人提供)：骨形态发生蛋白(BMP)家族的分泌性信号分子在胚胎发育的不同阶段指导多种器官和组织的发育，并与先天性和成人疾病有关。通过在模型生物中的研究，人们已经对BMP信号的生理作用获得了巨大的见解，这极大地增强了我们对人类发育和疾病的理解。在这里，我们将探索BMP信号复合体的性质，它在原肠形成过程中起作用，沿着脊椎动物的背腹轴排列组织。长期目标是了解需要多个配体和受体来转导BMP信号的分子基础。其次，将研究沿着背腹和前后轴的图案的协调，检验这两个轴的图案是协调的假设。据推测，这种坐标模式导致了BMP的活性，随着时间的推移，沿着前后轴逐渐作用于背腹组织。最后，将研究一个新的隐性背靠背母性效应突变基因的分子性质和贡献，以通过功能丧失的研究来最大限度地了解BMP信号在发育和疾病中的遗传调节。因此，识别和研究这一过程中的所有遗传参与者是至关重要的。 公共卫生相关性：骨形态发生蛋白(BMP)和TGF2家族分泌的信号分子指导多种器官和组织类型的发育，并与先天性和成人疾病有关。正在进行的研究表明，在肾脏疾病、肺动脉高压、胰腺、结直肠和其他癌症的治疗中，以及在整形外科、牙髓和组织工程等医疗应用中，调节BMP和TGF2信号转导具有潜力。我们对BMP和TGF2信号在发育和疾病中的生理作用的理解需要深入研究它们的信号如何在无数的生物学背景下产生不同的细胞反应，这里将进行研究。

DESCRIPTION (provided by applicant): The Bone Morphogenetic Protein (BMP) family of secreted signaling molecules directs the development of multiple organs and tissue types at various stages in embryogenesis, and is implicated in congenital and adult diseases. Enormous insights into the physiologic roles of BMP signaling have been gained through their study in model organisms, which have vastly enhanced our understanding of human development and disease. Here the nature of the BMP signaling complex will be explored that functions during gastrulation to pattern tissues along the vertebrate dorsal- ventral axis. The long-term goal is to understand the molecular basis for the requirement for multiple ligands and receptors to transduce BMP signaling. Second the coordination of patterning along the dorsal-ventral and anterior-posterior axes will be investigated, testing the hypothesis that patterning of these two axes is coordinated. It is postulated that this coordinate patterning results in BMP activity acting progressively over time along the anterior-posterior axis to pattern dorsal-ventral tissues. Lastly, the molecular nature and contributions of a new recessive dorsalized, maternal-effect mutant gene, will be studied, to maximize our understanding of the genetic regulation of BMP signaling in development and disease through loss-of-function studies. Thus it is critical to identify and study all the genetic players in this process. Public Health Relevance: The Bone Morphogenetic Protein (BMP) and TGF2 family of secreted signaling molecules directs the development of multiple organs and tissue types and is implicated in congenital and adult diseases. Ongoing investigations suggest the potential for modulating BMP and TGF2 signaling in the treatment of disorders as diverse as kidney disease, pulmonary hypertension, pancreatic, colorectal, and other cancers, and in medical applications such as orthopedics, endodontics, and tissue engineering. Our understanding of the physiologic roles of BMP and TGF2 signaling in development and disease requires thorough studies of the means by which their signaling generates diverse cellular responses in a myriad of biological contexts, as will be studied here.