Hoshii Takayuki, Takeo Toru, Nakagata Naomi, Takeya Motohiro, Araki Kimi, Yamamura Ken-ichi
Division of Developmental Genetics, Institute of Molecular Embryology and Genetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan.
Biol Reprod. 2007 Feb;76(2):303-13. doi: 10.1095/biolreprod.106.054619. Epub 2006 Nov 1.
The roles of the leucine-rich repeat domain containing G protein-coupled receptor (GPCR) 4 (Lgr4), which is one of the orphan GPCRs, were analyzed with the Lgr4 hypomorphic mutant mouse line (Lgr4(Gt)). This homozygous mutant had only one-tenth the normal transcription level; furthermore, 60% of them survived to adulthood. The homozygous male was infertile, showing morphologic abnormalities in both the testes and the epididymides. In the testes, luminal swelling, loss of germinal epithelium in the seminiferous tubules, and rete testis dilation were observed. Cauda epididymidis sperm were immotile. Rete testis dilation was due to a water reabsorption failure caused by a decreased expression of an estrogen receptor (ESR1) and SLC9A3 in the efferent ducts. Although we found differential regulation of ESR1 expression in the efferent ducts and the epididymis, the role of ESR1 in the epididymis remains unclear. The epididymis contained short and dilated tubules and completely lacked its initial segment. In the caput region, we observed multilamination and distortion of the basement membranes (BMs) with an accumulation of laminin. Rupture of swollen epididymal ducts was observed, leading to an invasion of macrophages into the lumen. Male infertility was probably due to the combination of a developmental defect of the epididymis and the rupture of the epithelium resulting in the immotile spermatozoa. These results indicate that Lgr4 has pivotal roles to play in the regulation of ESR1 expression, the control of duct elongation through BM remodeling, and the regional differentiation of the caput epididymidis.
富含亮氨酸重复序列的G蛋白偶联受体（GPCR）4（Lgr4）属于孤儿GPCR，利用Lgr4低表达突变小鼠品系（Lgr4(Gt)）对其作用进行了分析。该纯合突变体的转录水平仅为正常水平的十分之一；此外，60%的突变体能够存活至成年。纯合雄性不育，睾丸和附睾均出现形态异常。在睾丸中，观察到管腔肿胀、生精小管中生发上皮缺失以及睾丸网扩张。附睾尾精子无运动能力。睾丸网扩张是由于输出小管中雌激素受体（ESR1）和SLC9A3表达降低导致水重吸收功能障碍所致。尽管我们发现输出小管和附睾中ESR1表达存在差异调节，但ESR1在附睾中的作用仍不清楚。附睾包含短而扩张的小管，且完全缺乏起始段。在附睾头区域，我们观察到基底膜（BM）多层化和扭曲，伴有层粘连蛋白积聚。观察到肿胀的附睾管破裂，导致巨噬细胞侵入管腔。雄性不育可能是由于附睾发育缺陷和上皮破裂导致精子无运动能力共同作用的结果。这些结果表明，Lgr4在ESR1表达调节、通过基底膜重塑控制管伸长以及附睾头区域分化中发挥着关键作用。
