Ureteric Bud Patterning

输尿管芽图案

• 批准号: 8384891
• 负责人: DORIS A HERZLINGER
• 金额: $ 27.81万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-15 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384891
• 关键词: Alleles; Birth; Bladder; Cell Lineage; Cephalic; Characteristics; Congenital Abnormality; Cues; Data; Defect; Development; Distal; Duct (organ) structure; Embryo; Embryonic Development; Encapsulated; Epithelial; Etiology; Event; Excision; Exhibits; Fibroblasts; Fibrous capsule of kidney; Gene Dosage; Genes; Genetic; Genetic Recombination; Genotype; Germ Lines; Human; In Vitro; Kidney; Knockout Mice; Mediating; Messenger RNA; Metanephric Diverticulum; Morphogenesis; Mus; Muscle; Muscle function; Mutant Strains Mice; Nephrons; Newborn Infant; Obstruction; Pathway interactions; Pattern; Pelvis; Phenotype; Positioning Attribute; Predisposition; Prevention; Process; Publishing; Regulation; Role; Signal Pathway; Signal Transduction; Site; Smooth Muscle; Staging; System; Technology; Testing; Tissues; Transcriptional Regulation; Tube; Ureter; Urinary tract; Urine; Waste Products; Work; cell type; cofactor; in vivo; insight; knock-down; mutant; nephrogenesis; prevent; progenitor; research study; urinary tract obstruction

ABSTRACT Mammalian renal development is dependent on the ureteric bud. Its proximal tip induces nephron formation in the developing kidney and undergoes branching morphogenesis forming the intra-renal collecting system whereas its distal or trunk domain differentiates into the ureter. Abnormal regulation of ureteric bud morphogenesis can result in a spectrum of congenital defects, the most common being ureteral duplications and obstructions. Yet the tissue interactions and signaling pathways that limit ureter number and control ureteral smooth muscle differentiation required for the un-obstructed flow of urine to the bladder remain poorly understood. This proposal is focused on ureter morphogenesis. In Aim 1, the role of Bmp signaling in restricting ureteric bud outgrowth to a single site along the urinary tract and in controlling ureteral smooth muscle differentiation will be analyzed in mice with a severe knockdown in Bmp4 gene dosage that supports embryonic viability to birth, but not beyond. Inducible Bmp4 knockdown will be accomplished using Cre-lox technology and existing mouse lines. Bmp4 will be knocked down at different stages of development to analyze the role of this signaling factor in regulating ureter number separately, from its role in controlling terminal ureter differentiation. In Aim 2, we will analyze a mouse line lacking expression of Pbx1, a hox gene cofactor. We have discovered that Pbx1 is essential for restricting Bmp4 signaling and smooth muscle formation to the ureter. This mutant line will be used to dissect the genetic pathways and cell type (s) that control the organization of smooth muscle at the border between the kidney and the ureter, the most common site of urinary tract obstructions in newborns. The successful completion of these experiments will provide insight into the susceptibility of ureter morphogenesis to congenital defects.

摘要 哺乳动物肾脏的发育依赖于输尿管芽。它的近端 在发育中的肾脏中诱导肾单位的形成并经历分支 形成肾内集合系统的形态发生，而其远端或躯干 区域分化为输尿管。输尿管芽调节异常 形态发生可导致一系列先天性缺陷，最常见的是 输尿管重复和梗阻。然而，组织间的相互作用和信号 限制输尿管数量和控制输尿管平滑肌分化的途径 对于尿流通畅到膀胱所需的条件仍知之甚少。 这项建议的重点是输尿管的形态发生。在目标1中，BMP信号的作用 将输尿管芽生长限制在沿尿路的单一位置和在 控制输尿管平滑肌分化将被分析在严重的 抑制Bmp4基因剂量，支持胚胎存活到出生，但不是 更远一点。可诱导的Bmp4击倒将使用Cre-lox技术和 现有的鼠标线。BMP4将在不同的发展阶段被淘汰，以 分别分析这一信号因子在调节输尿管数量中的作用。 在控制输尿管末端分化中的作用。在目标2中，我们将分析一条老鼠线 HOX基因辅因子Pbx1表达缺失。我们发现Pbx1是 对于限制Bmp4信号和输尿管的平滑肌形成是必不可少的。 这个突变系将被用来剖析遗传途径和细胞类型(S) 控制肾与肾交界处的平滑肌组织 输尿管，新生儿最常见的尿路梗阻部位。成功者 这些实验的完成将有助于深入了解输尿管的易感性。 先天缺陷的形态发生。