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.

（请保持文字，不要PDF） 在此处输入文本，这是您的应用程序的新摘要信息。此部分不得超过30行文本。 神经嵴祖细胞是自主神经系统中外周神经节发育所必需的。许多自主神经节的神经嵴祖细胞的分化控制过程是众所周知的。然而，对盆神经节内细胞谱系的形成知之甚少。控制盆腔自主神经元的神经发生、分化、多样化和成熟的调节过程尚不清楚。盆神经节在启动膀胱收缩和介导有效排空中起重要作用。因此，骨盆神经元的研究将有助于了解影响大部分人群的尿路疾病。在人类中，盆腔自主神经元主要分散在下腹下丛，而在啮齿动物中，盆腔神经元聚集到位于下尿路（LUT）旁边的主要盆腔神经节中。我们先前在小鼠中的LUT研究确定了当盆自主神经元分化和成熟时，转录因子Pax 3在胎儿和出生后盆神经节中的表达。由于Pax 3在发育过程中广泛表达，该基因的突变通常由于神经管缺陷而致命。我们产生了在神经嵴谱系中具有Pax 3缺失的小鼠的新品系。这些动物出生后存活，表现出膀胱壁神经支配缺陷，排尿模式改变。神经嵴限制性Pax 3突变体提供了一个令人兴奋的机会，以确定骨盆神经节形成的关键监管方面，并确定骨盆自主神经元的赤字与LUT功能障碍。在这项研究中，我们专注于产后阶段的盆神经节成熟测试以下假设：1 -Pax 3是必不可少的生产正常分配的神经元类型的小鼠主要盆神经节成熟产后。2 -神经嵴特异性Pax 3缺失减少了成熟时盆腔自主神经元的总数。将使用单细胞测序和高分辨率大规模显微镜检查评估与正常同窝仔相比，出生后Pax 3突变体中盆神经节的最终组成。研究结果将提供更好的了解如何改变盆腔神经支配有助于LUT功能障碍。