Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2
Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2
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DOI：
10.1073/pnas.0508881103
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发表时间：
2006-03-14
影响因子：
11.1
通讯作者：
Shigeyoshi, Y
中科院分区：
文献类型：
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作者：
Matsumoto, S;Yamazaki, C;Shigeyoshi, Y
前动力素是一种多功能分泌蛋白，可激活两种内源性G蛋白偶联受体PKR1和PKR2。从小鼠脑的原位分析中，我们发现PKR2主要在嗅球（OB）中表达。为了研究PKR2在OB中的作用，我们建立了PKR1和PKR2基因破坏的小鼠（分别为Pkr1（-/-）和Pkr2（-/-））。表型分析表明Pkr1（-/-）小鼠OB发育不全，而Pkr2（-/-）小鼠OB发育不全。在Pkr 2（-/-）小鼠胚胎OB的早期发育阶段观察到这种异常。此外，Pkr 2（-/-）小鼠表现出生殖系统的严重萎缩，包括睾丸、卵巢、子宫、阴道和乳腺。在Pkr 2（-/-）小鼠中，血浆睾酮和卵泡刺激素水平降低，下丘脑中促性腺激素释放激素和垂体中促黄体生成素和卵泡刺激素的mRNA转录水平也显著降低。免疫组织化学分析显示，Pkr 2（-/-）小鼠下丘脑中没有促性腺激素释放激素神经元。Pkr2（-/-）小鼠的表型显示出与Kallmann综合征的临床特征相似，Kallmann综合征是一种以低促性腺激素性性腺功能减退和嗅觉丧失相关为特征的人类疾病。我们目前的研究结果表明，PKR2的生理激活是OB和性成熟的正常发育所必需的。
Prokineticins, multifunctional secreted proteins, activate two endogenous G protein-coupled receptors PKR1 and PKR2. From in situ analysis of the mouse brain, we discovered that PKR2 is predominantly expressed in the olfactory bulb (OB). To examine the role of PKR2 in the OB, we created PKR1- and PKR2-gene-disrupted mice (Pkr1(-/-) and Pkr2(-/-), respectively). Phenotypic analysis indicated that not Pkr1(-/-) but Pkr2(-/-) mice exhibited hypoplasia of the OB. This abnormality was observed in the early developmental stages of fetal OB in the Pkr2(-/-) mice. In addition, the Pkr2(-/-) mice showed severe atrophy of the reproductive system, including the testis, ovary, uterus, vagina, and mammary gland. In the Pkr2(-/-) mice, the plasma levels of testosterone and follicle-stimulating hormone were decreased, and the mRNA transcription levels of gonadotropin-releasing hormone in the hypothalamus and luteinizing hormone and follicle-stimulating hormone in the pituitary were also significantly reduced. Immunohistochemical analysis revealed that gonadotropin-releasing hormone neurons were absent in the hypothalamus in the Pkr2(-/-) mice. The phenotype of the Pkr2(-/-) mice showed similarity to the clinical features of Kallmann syndrome, a human disease characterized by association of hypogonadotropic hypogonadism and anosmia. Our current findings demonstrated that physiological activation of PKR2 is essential for normal development of the OB and sexual maturation.