Neural crest-derived pelvic ganglia and the effects of developmental deficits on lower urinary tract innervation

神经嵴衍生的盆腔神经节和发育缺陷对下尿路神经支配的影响

• 批准号: 10719065
• 负责人: E Michelle SOUTHARD-SMITH
• 金额: $ 35万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719065
• 关键词: Affect; Age; Alleles; Animals; Autonomic ganglion; Autonomic nervous system; Bladder; Bladder Control; Bladder Dysfunction; Cell Lineage; Child; Coupled; Data; Defect; Development; Electric Stimulation; Equilibrium; Exhibits; Fetal Development; Functional disorder; Ganglia; Genes; Goals; Human; Hypogastric Plexus; Image; Immunohistochemistry; In Situ; Inferior; Knowledge; Laser Scanning Confocal Microscopy; Lower urinary tract; Mediating; Microscopy; Motor Neurons; Mus; Muscle; Mutation; Neural Crest; Neural Tube Defects; Neuroanatomy; Neuronal Differentiation; Neurons; Outcomes Research; Pattern; Pelvis; Peripheral; Peripheral Nervous System; Phenotype; Play; Population; Prevalence; Process; Public Health; Reaction; Recommendation; Research; Resolution; Rodent; Role; School-Age Population; Site; Stains; Testing; Text; Ureter; Urinary tract; Urination; Urogenital Sinus; Vertebral column; cell type; design; experience; fetal; ganglion cell; interest; lower urinary tract symptoms; mature animal; migration; mouse model; mutant; nerve supply; neurodevelopment; neurogenesis; novel; postnatal; progenitor; response; segregation; sex; single cell sequencing; single-cell RNA sequencing; transcription factor; urinary bladder neck; young adult

(PLEASE KEEP IN WORD, DO NOT PDF) Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Neural crest progenitors are essential for development of peripheral ganglia in the autonomic nervous system. Much is known about processes that control differentiation of neural crest progenitors for many autonomic ganglia. However, very little is known about formation of cell lineages within pelvic ganglia. Regulatory processes that control neurogenesis, differentiation, diversification, and maturation of pelvic autonomic neurons are undefined. Pelvic ganglia play essential roles in initiating bladder contraction and mediating efficient emptying. Thus, studies of pelvic neurons will inform understanding of urinary tract conditions that affect a large portion of the population. In humans, pelvic autonomic neurons are scattered primarily in the inferior hypogastric plexus, while in rodents pelvic neurons are aggregated into major pelvic ganglion situated alongside the lower urinary tract (LUT). Our prior LUT studies in mice identified expression of the transcription factor Pax3 in fetal and postnatal pelvic ganglia when pelvic autonomic neurons are differentiating and maturing. Because Pax3 is widely expressed during development, mutations in this gene are typically lethal due to neural tube defects. We generated novel lines of mice that have loss of Pax3 in neural crest lineages. These animals are postnatal viable and exhibit deficits of bladder wall innervation with altered voiding patterns. Neural-crest restricted Pax3 mutants offer an exciting opportunity to identify key regulatory aspects of pelvic ganglia formation and determine how deficits of pelvic autonomic neurons relate to LUT dysfunction. In this study we focus on postnatal stages of pelvic ganglia maturation to test the following hypotheses: 1 – Pax3 is essential for producing the normal allocation of neuron types as the mouse major pelvic ganglion matures postnatally. 2 – neural crest-specific loss of Pax3 reduces total numbers of pelvic autonomic neurons at maturity. Use of single-cell sequencing and high-resolution large-scale microscopy will be applied to assess the final composition of pelvic ganglia in postnatal Pax3 mutants compared to normal littermates. Research outcomes will provide greater understanding of how alterations in pelvic innervation contribute to LUT dysfunction.

（请保持言语，不要PDF） 在此处输入文本，这是您应用程序的新摘要信息。本节必须不超过30行文本。 神经rest祖细胞对于自主神经系统中周围神经节的发展至关重要。关于控制许多自主神经神经神经元素祖细胞的分化的过程知之甚少。但是，关于骨盆神经节内细胞谱系的形成知之甚少。控制骨盆自主神经元的神经发生，分化，多样化和成熟的调节过程是不确定的。骨盆神经节在发起膀胱收缩和介导有效的排空中起着至关重要的作用。这是对骨盆神经元的研究，将告知人们对影响大部分人群的尿路条件的理解。在人类中，骨盆自主神经元主要散布在下胃丛中，而在啮齿动物中，骨盆神经元被聚集成位于下尿路（LUT）的主要骨盆神经节中。我们先前在小鼠中的LUT研究鉴定了骨盆自主神经元在区分和成熟时，在胎儿和产后骨盆神经节中鉴定了转录因子PAX3的表达。由于PAX3在发育过程中广泛表达，因此由于神经元管缺陷，该基因中的突变通常是致命的。我们产生了新的小鼠线，这些小鼠在神经元峰谱系中丧失了PAX3。这些动物是产后可行的，并且表现出了膀胱壁神经的定义，并改变了空隙模式。神经克雷斯特限制的PAX3突变体提供了一个令人兴奋的机会，以识别骨盆神经节形成的关键调节方面，并确定定义盆腔自主神经元与LUT功能障碍有关的方式。在这项研究中，我们着重于骨盆神经节成熟的产后阶段，以检验以下假设：1 - PAX3对于作为小鼠主要的骨盆神经节在出现后的小鼠骨盆中的正常分配而言至关重要。 2 - 神经元特异性PAX3的特异性损失减少了成熟时骨盆自主神经元的总数。与正常同窝仔相比，使用单细胞测序和高分辨率大型显微镜的使用将用于评估产后PAX3突变体中骨盆神经节的最终组成。研究成果将对骨盆神经的改变如何有助于LUT功能障碍。