Dorsal-Ventral Pattern Formation in the Zebrafish Embryo

产品描述（申请人提供）：信号传导在胚胎发生中指导多种器官和组织的发育，是多种先天性和成人疾病的致病因素。许多研究表明，在治疗如肾病、肺动脉高压等多种疾病以及在整形外科、牙髓病学和组织工程等医学应用中调节BMP信号传导的潜力。BMP异源二聚体由于其对BMP同源二聚体更高的信号传导活性和在治疗方面的潜力而受到越来越多的关注。为了了解BMP信号传导如何在无数生物学背景下产生不同的细胞反应并影响疾病，以及BMP异源二聚体如何最有效地用于治疗，必须了解BMP信号传导的机制。BMP信号在脊椎动物发育中的一个关键功能是在囊胚和原肠胚晚期沿背腹（DV）胚胎轴沿着排列细胞。BMP信号传导活性被认为充当形态发生素，以不同的活性水平指定不同的细胞类型。背侧散发的BMP拮抗剂在产生BMP活性梯度方面是重要的，其中背侧具有低水平，腹侧具有最高水平。在先前的授权期间，发现BMP异二聚体仅在斑马鱼DV图案化中发出信号，提供了脊椎动物中BMP异二聚体信号传导的体内生理测定。本文的研究将使用这种独特的体内动物模型来阐明导致斑马鱼DV模式中BMP异二聚体的排他性信号传导的机制。预期该结果与其他生物学背景下的BMP异二聚体信号传导机制广泛相关。 一个知之甚少的机制限制BMP拮抗剂的背侧区域在囊胚后期阶段。在过去的补助金期间，在斑马鱼中确定了一种新的遗传调节剂，当缺乏时，会导致BMP拮抗剂和背中线中胚层的腹侧扩张，导致多个背轴的戏剧性形成。该突变基因编码整合子复合物亚基6（ints6），代表了该基因在任何生物体中研究的第一个功能丧失突变。这些研究将在这里扩展，以确定Ints6如何与DV模式的其他母体调节因子一起发挥作用，以阐明其作用机制。最后，将研究具有类似于ints6的缺陷的新母体效应突变基因的分子性质和所起的作用。据推测，它编码一个新的基因或一个已知的基因与DV图案的新功能，这将允许介导脊椎动物DV图案的分子机制的阐述。!

DESCRIPTION (provided by applicant): signaling directs the development of multiple organs and tissues in embryogenesis, and is the causative factor in multiple congenital and adult diseases. Numerous studies suggest the potential for modulating BMP signaling in the treatment of disorders as diverse as kidney disease, pulmonary hypertension, and in medical applications such as orthopedics, endodontics, and tissue engineering. BMP heterodimers are receiving increasing attention recently due to their higher signaling activity to BMP homodimers and their potential in therapeutics. To understand how BMP signaling can generate diverse cellular responses in a myriad of biological contexts and affect disease, as well as how BMP heterodimers can be most effectively used in therapeutics, it is imperative to understand the mechanism by which BMPs signal. A key function of BMP signaling in vertebrate development is to pattern the cells along the dorsoventral (DV) embryonic axis during late blastula and gastrula stages. BMP signaling activity is thought to act as a morphogen, specifying distinct cell types at different activity levels. Dorsally-emanating BMP antagonists are important in generating the gradient of BMP activity with low levels dorsally and highest levels ventrally. In the previous grant period, BMP heterodimers were found to exclusively signal in zebrafish DV patterning, providing an in vivo, physiological assay in vertebrates for BMP heterodimer signaling. The studies here will use this unique in vivo animal model setting to elucidate the mechanism that leads to the exclusive signaling by BMP heterodimers in zebrafish DV patterning. The results are expected to be broadly relevant to BMP heterodimer signaling mechanisms in other biological contexts. A poorly understood mechanism restricts BMP antagonists to dorsal regions during late blastula stages. A new genetic regulator of this process in zebrafish was identified in the past grant period, which when deficient leads to the ventral expansion of BMP antagonists and dorsal midline mesoderm causing the dramatic formation of multiple dorsal axes. The mutant gene encodes the integrator complex subunit 6 (ints6), representing the first loss-of-function mutation of this gene to be studied in any organism. These studies will be extended here to determine how Ints6 functions with the other maternal regulators of DV patterning to elucidate its mechanism of action. Lastly, the molecular nature and role played by a new maternal-effect mutant gene with a defect similar to ints6 will be studied. It is postulated to encode a novel gene or an already known gene with a new function in DV patterning, which will allow the elaboration of the molecular mechanisms mediating vertebrate DV patterning. !