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.

（请以 WORD 形式保存，请勿以 PDF 形式保存） 在此处输入文本，该文本是您的应用程序的新摘要信息。此部分的文本长度不得超过 30 行。 神经嵴祖细胞对于自主神经系统周围神经节的发育至关重要。人们对控制许多自主神经节神经嵴祖细胞分化的过程了解很多。然而，人们对盆腔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。盆腔神经节在启动膀胱收缩和介导有效排空方面发挥着重要作用。因此，对盆腔神经元的研究将有助于了解影响大部分人群的尿路状况。在人类中，盆腔自主神经元主要分散在下腹下神经丛中，而在啮齿类动物中，盆腔神经元聚集在位于下尿路（LUT）旁边的主要盆腔神经节中。我们之前对小鼠进行的 LUT 研究发现，当盆腔自主神经元分化和成熟时，转录因子 Pax3 在胎儿和出生后盆腔神经节中表达。由于 Pax3 在发育过程中广泛表达，因此该基因的突变通常会因神经管缺陷而致命。我们培育了神经嵴谱系中 Pax3 缺失的新小鼠品系。这些动物出生后可存活，并表现出膀胱壁神经支配缺陷和排尿模式改变。神经嵴限制性 Pax3 突变体提供了一个令人兴奋的机会来识别盆腔神经节形成的关键调控方面，并确定盆腔自主神经元的缺陷与 LUT 功能障碍之间的关系。在本研究中，我们重点关注盆腔神经节成熟的产后阶段，以测试以下假设：1 – 随着小鼠盆腔主要神经节在产后成熟，Pax3 对于产生神经元类型的正常分配至关重要。 2 – Pax3 的神经嵴特异性缺失会减少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来评估出生后 Pax3 突变体与正常同窝小鼠相比的盆腔神经节的最终组成。研究成果将有助于更好地了解盆腔神经支配的改变如何导致 LUT 功能障碍。