Zhang F P, Poutanen M, Wilbertz J, Huhtaniemi I
Department of Physiology, Institute of Biomedicine, University of Turku FIN-20520, Turku, Finland.
Mol Endocrinol. 2001 Jan;15(1):172-83. doi: 10.1210/mend.15.1.0582.
To study further the role of gonadotropins in reproductive functions, we generated mice with LH receptor (LHR) knockout (LuRKO) by inactivating, through homologous recombination, exon 11 on the LHR gene. LuRKO males and females were born phenotypically normal, with testes, ovaries, and genital structures indistinguishable from their wild-type (WT) littermates. Postnatally, testicular growth and descent, and external genital and accessory sex organ maturation, were blocked in LuRKO males, and their spermatogenesis was arrested at the round spermatid stage. The number and size of Leydig cells were dramatically reduced. LuRKO females also displayed underdeveloped external genitalia and uteri postnatally, and their age of vaginal opening was delayed by 5-7 days. The (-/-) ovaries were smaller, and histological analysis revealed follicles up to the early antral stage, but no preovulatory follicles or corpora lutea. Reduced gonadal sex hormone production was found in each sex, as was also reflected by the suppressed accessory sex organ weights and elevated gonadotropin levels. Completion of meiosis of testicular germ cells in the LuRKO males differs from other hypogonadotropic/cryptorchid mouse models, suggesting a role for FSH in this process. In females, FSH appears to stimulate developing follicles from the preantral to early antral stage, and LH is the stimulus beyond this stage. Hence, in each sex, the intrauterine sex differentiation is independent of LH action, but it has a crucial role postnatally for attaining sexual maturity. The LuRKO mouse is a close phenocopy of recently characterized human patients with inactivating LHR mutations, although the lack of pseudohermaphroditism in LuRKO males suggests that the intrauterine sex differentiation in this species is not dependent on LH action.
为了进一步研究促性腺激素在生殖功能中的作用，我们通过同源重组使促黄体生成素受体（LHR）基因的第11外显子失活，从而构建了LHR基因敲除小鼠（LuRKO）。LuRKO雄性和雌性小鼠出生时表型正常，其睾丸、卵巢和生殖器官结构与野生型（WT）同窝小鼠无异。出生后，LuRKO雄性小鼠的睾丸生长和下降、外生殖器及附属生殖器官成熟受阻，精子发生停滞在圆形精子细胞阶段。睾丸间质细胞的数量和大小显著减少。LuRKO雌性小鼠出生后外生殖器和子宫也发育不全，阴道开口年龄延迟5 - 7天。（-/-）卵巢较小，组织学分析显示卵泡发育至早期窦状卵泡阶段，但无排卵前卵泡或黄体。各性别性腺性激素分泌均减少，附属生殖器官重量减轻和促性腺激素水平升高也反映了这一点。LuRKO雄性小鼠睾丸生殖细胞减数分裂的完成情况与其他低促性腺激素性/隐睾小鼠模型不同，提示FSH在此过程中发挥作用。在雌性小鼠中，FSH似乎刺激卵泡从前窦状卵泡发育至早期窦状卵泡阶段，而LH是此阶段之后的刺激因素。因此，在各性别中，子宫内性别分化不依赖于LH作用，但出生后LH对于达到性成熟起关键作用。LuRKO小鼠与最近报道的具有LHR失活突变的人类患者表现极为相似，尽管LuRKO雄性小鼠缺乏假两性畸形，提示该物种子宫内性别分化不依赖于LH作用。
