GENETIC CONTROL OF EARLY TESTICULAR DESCENT

在人类种群中，3-4%的男性在出生时发生隐睾，使这种异常成为新生男孩中最常见的先天性出生缺陷。睾丸位置异常的两个主要后果是由精原细胞退化引起的不育和成年后患恶性肿瘤的高风险。睾丸下降在发育过程中是一个复杂的，多阶段的过程，其中男性性腺向阴囊发展。这一过程任何阶段的失败都会导致隐睾或睾丸不全。这项建议的长期目标是确定控制睾丸下降早期阶段分子机制的关键遗传成分。贝勒医学院（Baylor College of Medicine）发现的一种新的小鼠突变——crsp（隐睾伴斑点），将被用作研究这一问题的模型系统。纯合子的雄性小鼠具有较高的腹内睾丸位置，这与在增殖早期精子发生完全停止有关。我们的初步数据表明，这种突变并不特别影响精子发生，而是在发育过程中影响睾丸下降。它是由转基因插入到小鼠5号染色体的端粒区产生染色体DNA的缺失引起的。我们将关键基因组区域克隆到一系列重叠的BAC克隆中，并估计了缺失的物理距离。目前的应用是为了验证这样的假设，即crsp突变破坏了睾丸下降的早期决定因素之一，而crsp基因的功能障碍可能是导致突变体隐睾的原因。具体目的是：1)表征突变小鼠的表型和分子遗传重排；2)鉴定关键区域内的基因；3)通过BAC转基因拯救和基因缺陷突变体的产生，评估小鼠潜在候选基因。由此产生的信息将为阐明CRSP基因在隐睾病因学中的功能、确定与疾病相关的CRSP发育途径、开发新的诊断工具和未来治疗途径提供框架，以治疗这种男性最常见的出生缺陷。

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 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, multi-stage 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 intra abdominal position of the testes, associated with complete arrest of spermatogenesis in the early stages of proliferation. Our preliminary data have 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. We have 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 of 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 phenotype and 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. 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 disorder and development of new diagnostic tools and future therapeutic routes for this most common birth defect in men.