隐睾是小儿泌尿生殖系统常见畸形及男性不育的病因之一。课题组前期研究发现隐睾患儿中Fam13c基因多个新突变；突变mRNA导致斑马鱼胚胎原始生殖细胞迁移紊乱；Fam13c敲除小鼠及突变频率最高的P181L(小鼠中为P201L)突变小鼠(目前均只有杂合子)发生隐睾、雄激素受体Ar及特异表达于睾丸间质细胞并调控睾丸下降的关键因子Insl3等表达降低、细胞凋亡增加、精子前向运动能力降低且畸形率增加、以及cAMP和Actin信号通路异常等。由此我们提出假说：Fam13c在睾丸及精子发育中具有重要功能；P181L等突变可能通过Insl3/Rxfp2-cAMP、Ar-Actin及细胞凋亡信号通路等导致隐睾及精子异常。本课题拟通过分子、细胞和动物模型的系统性深入研究，阐明Fam13c在睾丸和精子发育中的功能及Fam13c突变导致隐睾和精子异常的分子机制。研究结果将为隐睾及男性不育的防治提供新方向和新靶点。

Cryptorchidism is a common urogenital malformation in children that is associated with male infertility. We have identified several mutations in the Fam13c gene in cryptorchidism patients. Injection of these mutant Fam13c mRNAs into zebrafish embryos resulted in primordial germ cell migration disorder. The Fam13c gene knockout mice and the Fam13c P201L (corresponding to the most frequent human Fam13c P181L mutation) knock-in mice (currently only heterozygous mice available) displayed phenotype of cryptorchidism which was associated with decreased expression of the testicular descent key factor Insl3 and its receptor Rxfp2 and androgen receptor Ar, and increased apoptosis in the testis. Transcriptome analysis revealed abnormality in the cAMP and actin signaling pathways. Based on these preliminary results, we hypothesize that Fam13c plays an important role in testis development and spermatogenesis, and mutation of which may contribute to the pathogenesis of cryptorchidism and male infertility through the Insl3/Rxfp2-cAMP, Ar-actin and apoptosis pathways. In this application, we will systematically study the function of Fam13c in testis development and spermatogenesis, and the mechanism of Fam13c mutations in causing cryptorchidism and sperm abnormalities. The outcomes will provide important information for new avenues and targets for prevention and therapy for cryptorchidism and male infertility.