权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The Role of E3-Ubiquitin Ligase Complex in Genitourinary Tract Development and Function.

E3-泛素连接酶复合物在泌尿生殖道发育和功能中的作用。

基本信息

批准号：
10349531
负责人：
Abhishek Seth
金额：
$ 20.66万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-25 至 2022-07-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10349531
关键词：
16p11.2 Actins Affect Androgen Receptor Birth CUL3 gene Cell Line Complex Congenital Abnormality Copy Number Polymorphism Critical Pathways Cryptorchidism Cytoskeleton Data Defect Development Diagnosis Diagnostic Reagent Kits Disease Essential Genes Exhibits Feminization Gametogenesis Gene Dosage Gene Targeting Genes Genetic Genital Genitalia Genitourinary system Germ Cells Goals High Prevalence Human Hypospadias In Vitro Incidence Individual Intercellular Junctions Knockout Mice Knowledge Lead Lesion Link Maintenance Male Genital Organs Malignant Neoplasms Masculine Mediating Molecular Mus Mutant Strains Mice Mutation Neurologic Newborn Infant Pathway interactions Patients Physiological Play Proteins RBX1 gene RHOA gene Receptor Signaling Recovery Regulation Risk Role Seminal Vesicles Sex Behavior Sex Differentiation Signal Transduction Testing Testis Tissues Ubiquitination Up-Regulation Urinary tract Urination Virilism cell motility design experimental study gonad development in vitro Model in vivo knock-down mRNA Expression male mouse model overexpression penis receptor expression sertoli cell sex development disorder subfertility tool ubiquitin-protein ligase urogenital tract

项目摘要

Summary: Despite their high prevalence, the molecular basis for common genitourinary (GU) congenital defects is poorly understood. We have identified and validated gene lesions at the KCTD13/16p11.2 locus as responsible for lower GU tract abnormalities, particularly cryptorchidism and hypospadias. KCTD13 encodes a substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex, which regulates the actin cytoskeleton and cell migration via ubiquitination and degradation of RHOA. Notably, RHOA has been implicated in the maintenance of Sertoli-germ cell junctions to promote gametogenesis and gonads development. E3 ubiquitin ligases also regulate the androgen receptor (AR), which is key to male genitalia development and differentiation. We found that KCTD13 is robustly expressed in the GU tract and have recently shown that in comparison to normal controls, gene copy number variants are remarkably common in patients with GU birth defects. Moreover, we obtained in vitro and in vivo evidence that KCTD13 loss affects AR levels in testis and penis. We also observed that haploinsufficient and Kctd13 deficient mice had significantly higher incidence of cryptorchidism and decreased size of testes, seminal vesicles and penis size in conjunction with spermatogenic defects, causing severe subfertility. Further, Kctd13 null mice revealed a significant decrease in masculinization factor SOX9 levels and concomitant upregulation of the feminization factor RHOA. While our collective data suggest a key role of KCTD13 in male GU development, the mechanisms of how this molecule impinges upon the AR and/or SOX9 axes remain a major gap of knowledge. We hypothesize that gene dosage changes in KCTD13 alter the signaling of the masculinization axes, leading to abnormal GU tract development, defective gonad formation, undervirilization, and subfertility. In line with our reasoning, we will test two plausible independent mechanisms by which KCTD13 mediates lower GU tract development and differentiation. First, we hypothesize and test that gene dosage changes in KCTD13 affect GU tract development by affecting AR degradation, subcellular localization and downstream gene targets (AIM 1). Second, we hypothesize and test that KCTD13 affects the expression of masculinization factor SOX9 directly by modulating SOX9 ubiquitination or indirectly by regulating RHOA degradation, which in turn leads to defects in testis and penile development and differentiation (AIM 2). Finally, we identify and characterize the mutations in KCTD13- CUL3 pathway that are critical in GU development such that they could be used to generate a diagnostic kit for patients with disorders of sexual development (AIM3). Completion of the studies in this proposal will advance our understanding of the molecular mechanisms that underlie common GU birth defects.

摘要：尽管常见泌尿生殖系统（GU）先天性缺陷的发生率很高，但其分子基础