Regulation of morphogen signaling at the plasma membrane: Novel components and interactions in the formation of graded BMP signaling in Drosophila wing imaginal discs

器官生长和通过分泌的信号分子的梯度形成图案，即所谓的形态起源，是动物发育的基本原则。在过去的二十年里，作为翅膀的幼虫前体的果蝇的翅膀想象盘已经成为研究形态原信号的性质和功能的一个特别重要的范例。在这个组织中，配体Decapentaplegic(DPP；果蝇BMP超家族的配体)沿着前后轴协调长距离、分级的BMP信号，为上皮细胞提供位置信息。人们对建立和维持适当的形态原信号的分子机制知之甚少。我们最近在这个系统中的工作最终确定了分泌蛋白五角体(PENT)，它与Glypicans一起调节BMP信号梯度的形状。在随后的研究中，我们发现了两个迄今尚未确定的跨膜蛋白，它们可能与pent和glypicans协同作用，通过调节配体分布和配体-受体相互作用来调节BMP形态发生。总之，这些发现表明，存在一个复杂的蛋白质网络，调节质膜上的形态原信号。这项拟议的研究旨在确定该网络的其他组成部分，并了解其在形态原信号调节中的分子功能。

Organ growth and patterning by gradients of secreted signaling molecules, so-called morphogens, is a fundamental principle in animal development. Over the last two decades, the wing imaginal disc of Drosophila, the larval precursor of the wing, has emerged as a particularly important paradigm for studying properties and functions of morphogen signaling. In this tissue, the ligand Decapentaplegic (Dpp; a drosophila ligand of the BMP superfamily) orchestrates long-range, graded BMP signaling along the anterior-posterior axis to equip cells of the epithelium with positional information. Relatively little is known about the molecular mechanisms that establish and maintain proper morphogen signal-ing. Our recent work in this system culminated in the identification of the secreted protein Pentagone (Pent) that, together with glypicans, regulates the shape of the BMP signaling gradient. In subsequent studies we have identified two hitherto uncharacterized transmembrane proteins that might work in concert with Pent and glypicans in the regulation of BMP morphogen by regulating ligand distribution and ligand-receptor interactions. Altogether, the findings suggest the existence of a complex network of proteins that regulate morphogen signaling at the plasma membrane. The proposed research aims at identifying additional components of the network and understanding its molecular function in the regulation of morphogen signaling.