Diversification of cell types during male and female external genital development

男性和女性外生殖器发育过程中细胞类型的多样化

• 批准号: 10491225
• 负责人: MARTIN J COHN
• 金额: $ 34.3万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491225
• 关键词: Affect; Anatomy; Androgens; Animal Model; Appearance; Atlases; Back; Birth; Buffers; Cells; Clitoris; Complication; Congenital Abnormality; Data; Defect; Development; Disease; Embryo; Endocrine Disruptors; Environmental Risk Factor; Estrogens; Failure; Female; Folic Acid; Four Core Genotypes; Genes; Genetic; Genetic Models; Genital; Genitalia; Genitourinary system; Goals; Gonadal Steroid Hormones; Growth; Hormonal; Hormones; Human; Hypospadias; In Situ Hybridization; Incidence; Knowledge; Link; Location; Male Genital Organs; Maps; Mediating; Metals; Methods; Molecular; Mus; Neural Tube Defects; Operative Surgical Procedures; Organ; Prevalence; Prevention; Prevention strategy; RNA; Reporting; Role; Sex Chromosomes; Sex Differences; Sex Differentiation; Side; Specific qualifier value; Structure; Surgical complication; Three-Dimensional Imaging; Tissues; Transcriptional Regulation; Transgenic Organisms; Treatment outcome; Tube; Urethra; Validation; Visualization; XX male; XY females; ambiguous genitalia; cell type; computerized tools; embryo tissue; epidemiologic data; epigenomics; external genitalia; fetal; gene function; imaging approach; imaging modality; improved; innovation; innovative technologies; male; mouse model; nanoscale; novel; penis; prevent; reconstruction; sex; sexual dimorphism; single molecule; single-cell RNA sequencing; surgery outcome; transcriptomics; virtual

This proposal for the GenitoUrinary Development Molecular Anatomy Project (GUDMAP) will use the mouse model to investigate how differences between male and female external genitalia arise at the single cell level. Congenital malformations of the external genitalia (CAEG) are among the most prevalent human birth defects, affecting ~1:150 live male births. Hypospadias is a CAEG that is characterized by ectopic opening(s) of the urethra on the ventral side of the penis. In severe hypospadias, the urethral plate can open along the entire underside of the penis, giving it a clitoris-like appearance. This condition is termed ambiguous genitalia. Genetic causes of hypospadias have been elusive. The global prevalence has led to increased scrutiny of environmental factors, particularly endocrine disrupting chemicals (EDCs) that can induce genital anomalies in animal models. Sexual differentiation of the embryonic genital tubercle (GT) into a penis or a clitoris is regulated by gonadal androgens and estrogen. The central role of sex hormones in GT development creates sensitivity to EDCs; however, the mechanisms that mediate EDC effects on the GT are unknown, particularly at a cellular level. Do EDCs that cause hypospadias act on all cells in the GT, or do they target specific cell types? If subpopulation(s) of hormonally-responsive cells control urethragenesis, then buffering those cells against EDCs could be a method for prevention of hypospadias (analogous to folic acid’s ability to prevent neural tube defects). For genetic hypospadias, identifying cell-specific gene functions can distinguish direct regulators of urethragenesis from genes with indirect effects (e.g. sensitivity to EDCs). Understanding cell type diversity in developing external genitalia is essential for identifying the causes of CAEG and for developing preventative strategies. A major obstacle to progress in prevention and treatment of CAEG is the lack of knowledge of the specific cell types in external genital tissues. This project aims to fill these critical knowledge gaps by using single cell RNA-sequencing combined with novel imaging modalities to map cell type diversity in the developing external genitalia of normal male and female mice.

这项关于生殖器发育分子解剖学项目(GUDMAP)的提案将使用小鼠模型来研究男性和女性外部生殖器之间的差异是如何在单细胞水平上产生的。先天性外生殖器畸形(CAEG)是人类最常见的出生缺陷之一，影响约1：150的男性活产。尿道下裂是一种以阴茎腹侧异位开口(S)为特征的CAEG。对于严重的尿道下裂，尿道板可以沿着整个阴茎下侧打开，使其看起来像阴蒂一样。这种情况被称为外阴不清。尿道下裂的遗传原因一直难以捉摸。全球流行导致了对环境因素的更严格的审查，特别是可以在动物模型中导致生殖器异常的内分泌干扰物(EDCs)。胚胎生殖器结节(GT)向阴茎或阴蒂的性别分化受性腺雄激素和雌激素的调节。性激素在GT发育中的核心作用产生了对EDC的敏感性；然而，调节EDC对GT影响的机制尚不清楚，特别是在细胞水平上。引起尿道下裂的内分泌细胞是作用于GT中的所有细胞，还是针对特定类型的细胞？如果激素反应细胞亚群(S)控制着尿路生成，那么缓冲这些细胞对内皮细胞的作用可能是预防尿道下裂的一种方法(类似于叶酸防止神经管缺陷的能力)。对于遗传性尿道下裂，识别细胞特有的基因功能可以区分直接调节尿路生成的基因和具有间接影响的基因(例如，对内皮细胞的敏感性)。了解外生殖器发育过程中细胞类型的多样性对于确定CAEG的原因和制定预防策略至关重要。在预防和治疗CAEG方面取得进展的一个主要障碍是缺乏对外生殖器组织中特定细胞类型的了解。该项目旨在通过使用单细胞RNA测序与新的成像模式相结合来填补这些关键的知识空白，以绘制正常雄性和雌性小鼠外生殖器发育中的细胞类型多样性图。