The role of Sprouty genes in development of mammalian external genitalia

Sprouty 基因在哺乳动物外生殖器发育中的作用

• 批准号: 8445140
• 负责人: Ophir D Klein
• 金额: $ 15万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-18 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445140
• 关键词: Address; Affect; Behavior; Biological; Birth; Cell Differentiation process; Cell Line; Cell physiology; Cells; Clinical; Congenital Abnormality; Data; Defect; Development; Distal; Embryo; Enzymes; Epithelial; Epithelium; Equilibrium; Etiology; Exhibits; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Genes; Genital system; Genitalia; Glans of clitoris; Glans penis; Goals; Hypersensitivity; Hypospadias; Image; Kidney; Knock-out; Knowledge; Lead; Life; Limb structure; Lung; MAP Kinase Gene; Measures; Mediating; Mesenchymal; Modeling; Molecular; Monitor; Morphogenesis; Mus; Mutant Strains Mice; Operative Surgical Procedures; Organ; Organogenesis; PI3K/AKT; Pathway interactions; Patients; Pattern; Phenotype; Play; Prenatal Diagnosis; Prevention; Process; Protein Tyrosine Kinase; Receptor Protein-Tyrosine Kinases; Regulation; Retinoic Acid Receptor; Role; Side; Signal Transduction; Signaling Molecule; Supplementation; Testing; Tooth structure; Tretinoin; Tube; Tubular formation; Urethra; appendage; base; constriction; external genitalia; improved; inhibitor/antagonist; innovation; insight; loss of function mutation; male; malformation; morphogens; mutant; reconstruction; research study; transcription factor

DESCRIPTION (provided by applicant): Mammalian external genital development requires a tightly coordinated network of signaling molecules and transcription factors. The Fibroblast Growth Factor (FGF) family of receptor tyrosine kinase (RTK) signaling molecules plays a central role in formation of the genital tubercle, which is the anlage of the glans penis and clitoris. Therefore, determining how the FGF pathway is regulated in the genital tubercle and which other pathways it interacts with will be critical to understanding the cellular mechanisms underlying malformations of the external genitalia. Sprouty (Spry) genes are important inhibitors of RTK signaling molecules, including FGFs. Loss of function mutations in Sprouty genes lead to hypersensitivity to FGF signaling, often resulting in abnormal cellular function and causing defects in several organs, including lungs, kidneys, teeth, and limbs. The regulation of FGF signaling by Sprouty genes led us to hypothesize that Sprouty genes play an important role in patterning of the external genitalia. We have recently found that combined deletion of Spry1 and Spry2 in mice results in hypospadias, a congenital anomaly in which the urethral meatus is abnormally placed along the ventral side of the glans penis rather than at the distal tip. Hypospadias is one of the most common birth defects, affecting approximately 1 in every 250-300 live male births. This condition, whose molecular etiology is poorly understood, can result in severe psycho-sexual problems and voiding abnormalities in spite of the best efforts at surgical reconstruction. Thus, there is a need for improved understanding of the etiology of the condition that could lead to better prenatal diagnosis as well as prevention and improved treatments. In this application, we will investigate how Sprouty genes control organogenesis of the mammalian external genitalia. By performing these studies, we will obtain fundamental insights into normal and abnormal genital tubercle morphogenesis. PUBLIC HEALTH RELEVANCE: Hypospadias is one of the most common birth defects, affecting approximately 1 in every 250-300 live male births. This condition, whose molecular etiology is poorly understood, can result in severe psycho-sexual problems and voiding abnormalities in spite of the best efforts at surgical reconstruction. Thus, knowledge about the molecular pathways controlling genital development is of major clinical importance, and the experiments in this R01 application will enhance our knowledge of these pathways.

描述（由申请人提供）：哺乳动物外生殖器发育需要一个紧密协调的信号分子和转录因子网络。受体酪氨酸激酶（RTK）信号分子的成纤维细胞生长因子（FGF）家族在生殖器结节的形成中起核心作用，生殖器结节是阴茎头和阴蒂的原基。因此，确定FGF途径如何在生殖器结节中调节以及与哪些其他途径相互作用对于了解外生殖器畸形的细胞机制至关重要。Sprouty（Spry）基因是RTK信号分子（包括FGF）的重要抑制剂。Sprouty基因的功能缺失突变会导致对FGF信号传导的超敏反应，通常导致细胞功能异常并导致多个器官（包括肺、肾脏、牙齿和四肢）的缺陷。通过Sprouty基因调节FGF信号传导使我们假设Sprouty基因在外生殖器的图案形成中起重要作用。我们最近发现，小鼠中Spry 1和Spry 2的联合缺失导致尿道下裂，这是一种先天性异常，其中尿道口异常地沿着阴茎头的腹侧放置，而不是在远端。尿道下裂是最常见的出生缺陷之一，每250-300个活产男婴中约有1个受到影响。这种情况，其分子病因学知之甚少，可导致严重的性心理问题和排尿异常，尽管在外科重建的最佳努力。因此，有必要提高对疾病病因的理解，这可能会导致更好的产前诊断以及预防和改善治疗。在本申请中，我们将研究Sprouty基因如何控制哺乳动物外生殖器的器官发生。通过这些研究，我们将获得基本的见解正常和异常生殖器结节形态发生。 公共卫生相关性：尿道下裂是最常见的出生缺陷之一，每250-300例活产男婴中约有1例受到影响。这种情况，其分子病因学知之甚少，可导致严重的性心理问题和排尿异常，尽管在外科重建的最佳努力。因此，有关控制生殖器发育的分子途径的知识具有重要的临床意义，R 01应用中的实验将增强我们对这些途径的了解。