Cell Growth and Differentiation in the Vetebrate Embryo

描述（由申请方提供）：小鼠原肠胚的定义特征 是原始条纹，一种动态结构， 进入以产生新生中胚层和内胚层。命运图谱研究 揭示了原始条纹可以分为三个功能 区域：产生生殖细胞和胚外细胞的近端条纹 中胚层;产生心脏中胚层和淋巴结衍生的远端条纹 轴向中内胚层;和产生非中线树干的中间条纹 中胚层小鼠的突变体amn不仅会损害外胚层的生长， 而且还特别地破坏了中间层的组装和/或功能 原始的血统最近对Amn基因的鉴定表明， 编码一种新的I型跨膜蛋白，其特异性表达于 原肠胚形成期间的内脏内胚层。因此，Amn必须作用于细胞 内脏内胚层非自主地控制上胚层细胞的行为 所需的增长和规范的中间原始条纹。的 Amn的胞外区包括富含半胱氨酸（CR）的基序， 与蛋白质中的BMP结合CR模块，如Chordin，已知作为 BMP信号传导的调节剂。这些发现表明，Amn可能直接 上胚层生长和产生的中间条纹衍生的树干中胚层， 其作用是调节下层内脏内胚层中的BMP信号通路。 这个工作模型将通过生物化学， 在培养的哺乳动物细胞，小鼠，非洲爪蟾， 和果蝇。此外，由外胚层细胞行为控制的外胚层细胞行为， 内脏内胚层中的“Amn途径”将通过克隆测序鉴定。 谱系分析和靶向转基因表达。有趣的是，另外两个 已知的Amn表达位点，肾近端小管和肠，如 内脏内胚层，极化上皮专门用于分泌， 再吸收在人类和果蝇中发现Amn同源物表明 Amn可能在发育中起着进化保守的作用， 这些特化细胞类型的分化或功能，通常是 人类疾病

DESCRIPTION (provided by applicant): The defining feature of the mouse gastrula is the primitive streak, a dynamic structure through which epiblast cells ingress to generate nascent mesoderm and endoderm. Fate mapping studies have revealed that the primitive streak can be divided into three functional regions: the proximal streak that gives rise to germ cells and extraembryonic mesoderm; the distal streak that generates cardiac mesoderm and node-derived axial mesendoderm; and the middle streak that produces non-midline trunk mesoderm. The mouse mutation amnionless (amn) not only impairs epiblast growth, but also specifically disrupts the assembly and/or function of the middle primitive streak. The recent identification of the Amn gene shows that it encodes a novel type I transmembrane protein that is specifically expressed in the visceral endoderm during gastrulation. Thus Amn must act cell non-autonomously in the visceral endodemi to govern epiblast cell behaviors required for growth and the specification of the middle primitive streak. The extracellular region of Amn includes a cysteine rich (CR) motif with similarity to BMP-binding CR modules in proteins, such as Chordin, known to act as modulators of BMP signaling. These findings suggest that Amn may direct epiblast growth and the production of middle streak-derived trunk mesoderm by acting to modulate a BMP signaling pathway in the underlying visceral endoderm. This working model will be explored though a combination of biochemical, genetic, and embryological studies in cultured mammalian cells, mice, Xenopus, and Drosophila. In addition, the epiblast cell behavior(s) controlled by the "Amn pathway" in the visceral endoderm will be identified through a clonal lineage analysis and targeted transgene expression. Intriguingly, the two other known sites of Amn expression, kidney proximal tubule and intestine, are, like the visceral endoderm, polarized epithelia specialized for secretion and resorption. The finding of Amn homologues in both human and Drosophila indicate the Amn likely plays an evolutionarily conserved role in the development, differentiation, or function of these specialized cell types, often targets of human disease.