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.

该泌尿生殖器发育分子解剖项目（GUDMAP）的这一建议将使用小鼠模型来研究男性和女性外生殖器之间的差异在单细胞水平上是如何出现的。外生殖器（CAEG）的先天性畸形是最普遍的人类出生缺陷之一，影响了〜1：150活着的男性出生。 Hypospadias是一个CAEG，其特征是阴茎腹侧尿道的尿道开口。在严重的催化性中，尿道板可以沿着阴茎的整个底面打开，使其具有阴蒂的外观。这种情况称为模棱两可的生殖器。降低造口的遗传原因是弹性的。全球流行率导致对环境因素的审查增加，尤其是内分泌破坏化学物质（EDC），这些化学物质（EDC）可能诱导动物模型中的生殖器异常。胚胎生殖器结节（GT）的性分子分化为阴茎或阴蒂，受性腺雄激素和雌激素调节。性骑士在GT开发中的核心作用对EDC产生了敏感性。但是，介导EDC对GT的介导的机制尚不清楚，尤其是在细胞水平上。引起催化性的EDC是否对GT中的所有细胞作用，还是针对特定细胞类型？如果荷尔蒙响应性细胞的亚群控制尿素发生，则将这些细胞缓冲到EDC上可能是预防降低性降低的一种方法（类似于叶酸预防神经管缺陷的能力）。对于遗传性降低，鉴定细胞特异性基因功能可以区分尿道促性的直接调节剂与具有间接作用的基因（例如对EDC的敏感性）。了解开发外部生殖器的细胞类型多样性对于确定CAEG的原因和制定预防策略至关重要。预防和治疗CAEG进展的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测序与新型成像方式相结合来填补这些关键的知识差距，以绘制正常雄性和雌性小鼠发展中的外部生殖器的细胞类型多样性。