Mechanisms of Veterbrate Dorsal-ventral Limb Patterning

描述（由申请人提供）：详细了解发育机制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。我们已经确定了这种畸形的根本原因，即影响指甲、髌骨和肘关节发育的指甲-髌骨综合征。LIM-同源结构域转录因子LMX 1B的突变引起的。我们在小鼠中的研究表明，Imxlb在背肢芽间充质中特异性表达，在那里它充当选择基因以指定背侧细胞命运。Imxlb表达如何被限制并维持在背肢芽间充质中，以及Imxlb调节背腹图案形成的机制知之甚少。在本研究中，我们将讨论三个主要问题。首先，我们将采用有条件的基因靶向Imx 1 B，以确定是否特定的间充质组织的子集协调肌肉骨骼图案的肢体。第二，我们将研究机制，负责背特异性表达的Imxlb的谱系追踪和转基因分析。最后，我们将测试ephrin/Eph信号通路作为Imxlb调节背腹肢芽发育的候选效应子。总之，这些实验将提供重要的洞察脊椎动物选择基因的功能，以协调调节一个复杂的发展计划。Lmxlb的活性也需要在身体的其他组织在发展和成人。从小鼠和人的研究中，我们知道Imx 1 B是肾脏和眼睛流出道的正常功能以及CMS的多巴胺能和多巴胺能系统的正常发育所必需的。这项拟议中的研究将提供有关Imxlb在肢体发育中的功能的信息，但也将揭示Imxlb如何调节肾脏、眼睛和大脑发育。由于LMX 1B突变的个体有肾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。

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.