Mechanisms of Veterbrate Dorsal-ventral Limb Patterning

脊椎动物背腹肢模式形成的机制

• 批准号: 8067104
• 负责人: Randy L. Johnson
• 金额: $ 30.34万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067104
• 关键词: Address; Adopted; Adult; Affect; Alleles; Axon; Brain; Cell Adhesion; Cell Separation; Cells; Complex; Congenital Abnormality; Connective Tissue; Development; Diagnosis; Dorsal; Ectopic Expression; Elbow; Ensure; Eph Family Receptors; EphA Receptors; Ephrins; Event; Eye; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Glaucoma; Human; Individual; Kidney; Kidney Failure; Knee bone; Laboratories; Ligands; Light; Limb Bud; Limb Development; Limb structure; Location; Logic; Maintenance; Maps; Mediating; Mesenchymal; Mesenchyme; Molecular; Morphology; Motor; Mus; Muscle; Musculoskeletal; Mutation; Nail plate; Nail-Patella Syndrome; Nervous system structure; Organ; Pathway interactions; Pattern; Play; Process; Protein Tyrosine Kinase; Regulation; Renal function; Research; Risk; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Structure; System; Testing; Time; Tissues; To specify; Transgenic Organisms; axonal pathfinding; developmental genetics; gene function; homeodomain; insight; loss of function; malformation; mutant; programs; research study; skeletal tissue; transcription factor

DESCRIPTION (provided by applicant): Detailed understanding of developmental mechanisms is essential to diagnose and treat congenital malformations. A common group of congenital malformations are those that affect limb development. We have defined underlying cause of one such malformation, nail-patella syndrome (NPS) that affects the development of the nails, patella, and elbow. NPS is caused by mutations in the LIM-homeodomain transcription factor LMX1B. Our studies in the mouse have indicated that Imxlb is expressed specifically in the dorsal limb bud mesenchyme where it acts as a selector gene to specify dorsal cell fates. How Imxlb expression is restricted to and maintained in the dorsal limb bud mesenchyme is poorly understood as is the mechanism(s) by which Imxlb regulates dorsal-ventral patterning. In the proposed research we will address three main issues. First, we will employ conditional gene targeting of Imx1 b to determine whether specific subsets of mesenchymal tissues coordinate musculoskeletal patterning of the limb. Second, we will examine mechanisms that are responsible for the dorsal-specific expression of Imxlb by lineage tracing and transgenic analysis. Finally, we will test the ephrin/Eph signaling pathway as a candidate effector of Imxlb in regulating dorsal-ventral limb bud development. Taken together, these experiments will provide significant insight into how vertebrate selector genes function to coordinate regulation of a complex developmental program. Lmxlb activity is also required in other tissues of the body both during development and in the adult. From studies in mice and humans we know that Imx1 b is required for proper functioning of the kidney and outflow tract of the eye as well as for proper development of the dopaminergic and serotonergic systems of the CMS. The proposed research will provide information about the function of Imxlb in limb development, but will also shed light into how Imxlb regulates kidney, eye, and brain development. As individuals with mutations in LMX1B are at risk for renal failure and glaucoma our research will also impact important heath concerns.

描述(由申请人提供)：对发育机制的详细了解对于诊断和治疗先天性畸形至关重要。一组常见的先天性畸形是那些影响肢体发育的畸形。我们已经确定了一种这种畸形的潜在原因，指甲-膝盖骨综合征(NPS)，它影响指甲、膝盖骨和肘部的发育。NPS是由LIM同源结构域转录因子Lmx1b突变引起的。我们在小鼠身上的研究表明，Imxlb在背侧肢芽间充质中特异表达，在那里它作为一个选择基因来指定背部细胞的命运。Imxlb在背侧肢芽间充质中的表达如何被限制和维持目前还不清楚，因为Imxlb调节背腹模式的机制(S)也是如此。在拟议的研究中，我们将解决三个主要问题。首先，我们将使用Imx1b的条件性基因打靶来确定特定的间质组织亚群是否与肢体的肌肉骨骼图案相协调。其次，我们将通过谱系追踪和转基因分析来研究导致Imxlb背部特异性表达的机制。最后，我们将测试EPhin/Eph信号通路作为Imxlb在调控背侧-腹侧肢芽发育中的候选效应者。综上所述，这些实验将为脊椎动物选择基因如何协调复杂发育程序的调节提供重要的洞察力。在发育过程中和成人体内的其他组织中也需要Lmxlb的活性。从对小鼠和人类的研究中，我们知道Imx1b对于肾脏和眼睛流出道的正常功能以及CMS的多巴胺和5-羟色胺能系统的正常发展是必需的。这项拟议的研究将提供有关Imxlb在肢体发育中的作用的信息，但也将阐明Imxlb如何调节肾脏、眼睛和大脑的发育。由于Lmx1b基因突变的个体面临肾功能衰竭和青光眼的风险，我们的研究也将影响重要的健康问题。

项目成果

An Lmx1b-miR135a2 regulatory circuit modulates Wnt1/Wnt signaling and determines the size of the midbrain dopaminergic progenitor pool.

• DOI: 10.1371/journal.pgen.1003973
• 发表时间: 2013
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Anderegg A;Lin HP;Chen JA;Caronia-Brown G;Cherepanova N;Yun B;Joksimovic M;Rock J;Harfe BD;Johnson R;Awatramani R
• 通讯作者: Awatramani R