GENETIC CONTROL OF EARLY TESTICULAR DESCENT

描述：（改编自研究者摘要）在人群中 隐睾发生在3-4%的男性在出生时，使这种异常， 新生男婴最常见的先天性出生缺陷。的两个主要后果 睾丸的异常位置是由睾丸变性引起的不孕症。 精原细胞和成年期恶性肿瘤的高风险。 睾丸发育过程中的下降是一个复杂的多阶段过程， 雄性生殖腺向阴囊前进。任何阶段的失败 过程导致隐睾或隐睾。长期 该提案的目标是确定控制基因的关键遗传成分， 睾丸下降早期的分子机制。一个新的鼠标 突变，crsp（隐睾与斑点），发现于贝勒大学， 医学，将作为一个模型系统来研究这个问题。雄性小鼠 CRSP纯合子具有较高的睾丸腹内位置， 与精子发生在早期阶段的完全停滞有关， 增殖初步数据显示，这种突变不会 特别影响精子发生，但在发育过程中影响睾丸下降。 它是由转基因插入到小鼠的端粒区引起的， 染色体5产生染色体DNA的缺失。PI克隆了 将关键基因组区域插入一系列重叠的BAC克隆中，并估计 删除的物理距离。本申请被设计为 测试crsp突变破坏了一种早期的 睾丸下降的决定因素和crsp基因的功能障碍， 突变型隐睾症的发生。具体目标是：1） 表征突变小鼠中的分子遗传重排; 2） 确定关键区域内的基因; 3）评估潜在的 通过BAC转基因拯救小鼠中的候选基因并产生 基因缺陷突变体; 4）鉴定和表征人CRSP基因。 由此产生的信息将提供一个框架，以阐明该职能 CRSP基因在隐睾病因学中的作用，CRSP基因的测定 发展途径有关的人类疾病和发展的新的 诊断工具和未来的治疗路线，为这一最常见的分娩 男人的缺点

DESCRIPTION: (adapted from Investigator's abstract) In human populations cryptorchidism occurs in 3-4% of males at birth, making this abnormality the most frequent congenital birth defect in newborn boys. Two main consequences of an abnormal location of the testis are infertility caused by degeneration of the spermatogonial cells and a high risk of malignant tumors in adulthood. Testicular descent during development is a complex, multistage process whereby the male gonads progress toward the scrotum. Failure in any stage of this process results in cryptorchidism or undescended testis. The long-term objectives of this proposal are to identify key genetic components that control the molecular mechanisms of the early phases of testicular descent. A new mouse mutation, crsp (cryptorchidism with spotting), discovered in Baylor College of Medicine, will be used as a model system to study this problem. Male mice homozygous for crsp have a high intraabdominal position of the testes, associated with complete arrest of spermatogenesis in the early stages of proliferation. Preliminary data has shown that the mutation does not specifically affect spermatogenesis but testicular descent during development. It is caused by a transgene insertion into the telomeric region of mouse chromosome 5 producing a deletion of the chromosomal DNA. The PI has cloned the critical genomic region into a series of overlapping BAC clones and estimated the physical distance of the deletion. The present application is designed to test the hypothesis that the crsp mutation disrupts one of the early determinants to testicular descent and that malfunction of the crsp gene could be responsible for the cryptorchidism in mutant. The specific aims are: 1) to characterize the molecular-genetic rearrangements in the mutant mice; 2) to identify genes residing within the critical region; 3) to evaluate potential candidate genes in mouse by BAC transgenic rescue and generation of gene-deficient mutants; 4) to identify and characterize the human CRSP gene. The resulting information will provide a framework for elucidating the function of the CRSP gene in the etiology of cryptorchidism, determination of the CRSP developmental pathways relevant to the human disorder and development of new diagnostic tools and future therapeutic routes for this most common birth defect in men.