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

基本信息

批准号：
10899817
负责人：
MARTIN J COHN
金额：
$ 7.56万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
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/10899817
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 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

项目摘要

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.

生殖泌尿发育分子解剖学项目 (GUDMAP) 的这项提案将使用小鼠模型来研究男性和女性外生殖器之间如何在单细胞水平上产生差异。先天性外生殖器畸形 (CAEG) 是人类出生时最常见的畸形之一。尿道下裂是一种 CAEG，其特征是阴茎腹侧尿道异位开口。在严重的尿道下裂中，尿道板可以沿着阴茎的整个下侧打开，使其具有阴蒂样的外观。尿道下裂的遗传原因一直难以捉摸，这导致了对环境的更多关注。因素，特别是内分泌干扰化学物质（EDC），可以在动物模型中诱导胚胎生殖结节（GT）性别分化为阴茎或阴茎。阴蒂受性腺雄激素和雌激素的调节。性激素在 GT 发育中发挥着重要作用，它对 EDC 产生敏感性；然而，介导 EDC 对 GT 影响的机制尚不清楚，尤其是在细胞水平上。 GT 中的所有细胞，还是它们针对特定细胞类型？如果激素反应性细胞亚群控制尿道形成，那么缓冲这些细胞对抗 EDC可能是预防尿道下裂的一种方法（类似于叶酸预防神经管缺陷的能力），识别细胞特异性基因功能可以区分尿道形成的直接调节因子和具有间接影响的基因（例如对 EDC 的敏感性）。外生殖器发育过程中细胞类型的多样性对于确定 CAEG 的病因和制定预防策略至关重要。预防和治疗 CAEG 进展的一个主要障碍是缺乏对特定细胞的了解。该项目旨在通过使用单细胞 RNA 测序结合新颖的成像方式来绘制正常雄性和雌性小鼠发育中的外生殖器的细胞类型多样性，从而填补这些关键的知识空白。