miRNA和遗传因素在男性不育发生中的功能研究
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摘要
不育困扰着10-15%的育龄夫妇,其中一半的因素来源于男性。尽管有数十种造成男性不育的病因学机制,但大多数男性不育的发生是原发性的。例如,很大比例的男性不育被诊断为不可解释的非梗阻性无精症(NOA)。进而,NOA患者通常具有较低的精子质量和临床受孕率。因此,阐明NOA潜在的分子发病机理将会限制促进男性不育的诊断和治疗。
精子发生是从精原干细胞发育到高度分化的精子细胞的过程,这个过程被严格调控。在精子发生减数分裂和单倍体形成时期,转录活性增加,翻译被抑制。这些时期的mRNA翻译抑制主要是通过转录后调控机制调控,其中就包括microRNA(miRNA).我们研究组已经报道microRNA-383(miR-383)在成熟抑制型(MA)男性不育患者的睾丸中显著下调,在本论文的首要研究目的就是阐明miR-383在MA型男性不育发生中潜在的分子机制。我们发现miR-383通过靶向肿瘤抑制因子interferon regulatory factor-1(IRF1)介导抑制细胞增殖、细胞周期G1期停滞和诱导细胞凋亡的效应,导致IRF1的下游靶基因Cyclin D1、CDK2、p21下调,而最终导致pRb磷酸化被抑制。这些结果将导致miR-383通过靶向IRF1、失活pRb而成为细胞增殖的负调因子。异常的miR-383表达可能成为连接男性不育和生殖细胞肿瘤的桥梁。
尽管上部分研究发现miR-383在MA型男性不育患者中下调,但miR-383的功能和靶向性是如何被调控的依旧未知。因此在本论文第二部分(第三章)的研究中,我们试图阐述miR-383在精子发生中的调控机理。我们发现FMRP在小鼠睾丸中结合包括miR-383在内的88个miRNAs。FMRP将通过抑制miR-383结合到其靶基因(IRF1(?)CyclinD1)的3’非编码区而提高miR-383诱导的细胞增殖抑制效应。另一方面,在NT-2和GC1(小鼠精原细胞系)中,FMRP的水平也被miR-383直接靶向Cyclin D1而下调。在Fmr1基因敲除小鼠睾丸中,我们发现miR-383表达下调、CDK4表达定位失调、DNA损伤增加等现象,而相似的现象在FMRP下调的MA型男性不育患者的睾丸中也被检测到。因而,FMRP-miR-383在精子发生中可以构成一个潜在的反馈调控回路,FMRP则扮演miR-383功能的负调因子角色。我们的研究成果也表明FMRP-miR-383调控通路的失调可能和MA型男性不育的发生密切相关。
另一方面,遗传因素也能影响男性不育。Kallmann综合症(KS)是一个遗传性进行性的失调疾病,症状为低促性腺激素功能减退症(导致不育)和嗅觉缺失／降低。由于在胚胎期的嗅球发育不全,神经内分泌细胞GnRH不能正常的沿着嗅神经纤维从鼻部向前脑迁移。现在已经发现大量的基因均与这种神经元的轴突导向相关,KS也被发现是一种遗传异质性疾病,涉及到多种遗传方式。但是,如今已经发现的致病基因只能解释近三分之一的KS患者的病因,还远远不能完全解释这种疾病,提示了还存在其他基因或调控通路参与到KS的发生中。在本论文的第三部分中,我们报道了一个汉族母系遗传KS家系。这个家系存在两个新发协同突变,分别是KAL1基因146G>T突变(p.49Cys>Phe)线粒体tRNAcysmt.5800A>G突变。进一步,线粒体cysteinyl-tRNA途径的失调能显著影响GnRH神经元细胞的体外迁移。而且,线粒体cysteinyl-tRNA转移酶Cars2基因也是调控斑马鱼GnRH3神经元迁移、幼鱼存活和斑马鱼嗅觉功能的关键因素。因此,在这部分我们提出了线粒体在GnRH(?)神经元迁移中起到重要的作用,为KS的遗传病因学提供了新的线索。
综上所述,本论文研究结果阐述了miR-383/FMRP反馈调控回路在精原细胞增殖凋亡调控和KAL1/线粒体半胱氨酸tRNA途径在Kallmann综合症中的功能。这些研究成果将为进一步理解精子发生缺陷和GnRH神经元迁移异常的分子调控机制奠定基础。
Infertility affects10-15%of couples who are trying to conceive, and half of the cases are due to male factors. Despite several decades of efforts to elucidate the etiologic mechanism of male infertility, most cases are idiopathic. For example, a significant proportion of male infertility is diagnosed as unexplained non-obstructive azoospermia (NOA). Furthermore, patients with NOA usually had a significantly lo-wer sperm retrieval rate and a clinical pregnancy rate. Therefore, elucidating the underlying molecular pathogenesis of NOA may help to improve treatment outcomes and therpies in these patients.
Spermatogenesis is a tightly regulated process during which spermatogonial stem cells develop into highly differentiated spermatozoa. The meiotic and haploid phases of spermatogenesis are characterized by high transcriptional activity but repressed translational activity. Translational repression of mRNAs in these phases must be achieved through a posttranscriptional regulatory mechanism, one of which is mediated by microRNAs (miRNAs). Our group had reported that miRNA-383expression is down-regulated in the testes of infertile men with maturation arrest (MA). So the first aim of this study was to understand the underlying mechanisms of miR-383involved in the pathogenesis of MA. miR-383targeted a tumor suppressor, interferon regulatory factor-1(IRF1), which in turn resulted in suppression of proliferation, cell-cycle arrest in G1phase and induction of apoptosis, a reduction of Cyclin D1, CDK2and p21levels, and an inhibition of pRb phosphorylation. These results suggest that miR-383functions as a negative regulator of proliferation by targeting IRF-1, in part, through inactivation of the pRb pathway. Abnormal testicular miR-383expression may potentiate the connections between male infertility and testicular germ cell tumor.
Although miR-383was expression is downregulated in the testes of infertile men with MA, how miR-383's functions and targeting were regulated in spermatogenesis still remained unknow. So in the second part of this study (Chapter Three), we were trying to elucilate the regulating mechanisms of miR-383during spermatogenesis. We found that FMRP was associated with88miRNAs in mouse testis including miR-383. FMRP enhanced miR-383-induced suppression of cell proliferation by decreasing the interaction between FMRP and miR-383and then affecting miR-383binding to the3'UTR of its target genes IRF1and Cyclin Dl. Furthermore, FMRP levels were also down-regulated by miR-383by targeting Cyclin D1directly. Reduced miR-383 expression, dysregulated CDK4expression and increased DNA damage were also observed in the testes of Fmrl knockout mice and of MA patients with a down-regulation of FMRP. A potential feedback loop between FMRP and miR-383during spermatogenesis is proposed, and FMRP acts as a negative regulator of miR-383functions. Our data also indicate that dysregulation of the FMRP-miR-383pathway may partially contribute to human spermatogenic failure with MA.
On the other hand, genetic factor also can affect male infertility. Kallmann syndrome (KS) is an inherited developmental disorder defined as the association of hypogonadotropic hypogonadism (causing male infertility) and anosmia or hyposmia. Due to olfactory bulb agenesis during embryonic development, the neuroendocrine GnRH cells fail to migrate from the nose to the forebrain along the olfactory nerve fibers.Various genes are involved the axonal pathfinding of the neurons, and KS has been shown to be a genetically heterogeneous disease with different modes of inheritance. However, mutations in any of the causative genes identified so far are only found in approximately one third of KS patients, thus indicating that other genes or pathways remain to be discovered. In the third part of this study, we report a large Han Chinese family with maternally inherited KS. The synergistic effect of mutations in KAL1(146G>T (p.49Cys>Phe))and mitochondrial tRNAcys(mt.5800A>G) can account for the occurrence of the disorder in this family. Furthermore, the disturbance of the mitochondrial cysteinyl-tRN A pathway can significantly influence the migration of GnRH cells in vitro. Also, Cars2is essential for the migration of GnRH3neurons, survival of larvae and sense of smell in zebrafish. Therefore, we propose that the mitochondria play important roles in the migration of GnRH cells and provide valuable clues to the genetic etiology of KS.
In summary, the results in this study revealed the role of miR-383/FMRP feedback pathway in control of spermatogonial proliferation and apoptosis, and mitochondrial cysteinyl-tRNA pathway in Kallmann syndrome. These results could help to further understanding of the underlying mechanisms of spermatogenesis failure and defects in GnRH nueron development in NO A and KS patients.
精子发生是从精原干细胞发育到高度分化的精子细胞的过程,这个过程被严格调控。在精子发生减数分裂和单倍体形成时期,转录活性增加,翻译被抑制。这些时期的mRNA翻译抑制主要是通过转录后调控机制调控,其中就包括microRNA(miRNA).我们研究组已经报道microRNA-383(miR-383)在成熟抑制型(MA)男性不育患者的睾丸中显著下调,在本论文的首要研究目的就是阐明miR-383在MA型男性不育发生中潜在的分子机制。我们发现miR-383通过靶向肿瘤抑制因子interferon regulatory factor-1(IRF1)介导抑制细胞增殖、细胞周期G1期停滞和诱导细胞凋亡的效应,导致IRF1的下游靶基因Cyclin D1、CDK2、p21下调,而最终导致pRb磷酸化被抑制。这些结果将导致miR-383通过靶向IRF1、失活pRb而成为细胞增殖的负调因子。异常的miR-383表达可能成为连接男性不育和生殖细胞肿瘤的桥梁。
尽管上部分研究发现miR-383在MA型男性不育患者中下调,但miR-383的功能和靶向性是如何被调控的依旧未知。因此在本论文第二部分(第三章)的研究中,我们试图阐述miR-383在精子发生中的调控机理。我们发现FMRP在小鼠睾丸中结合包括miR-383在内的88个miRNAs。FMRP将通过抑制miR-383结合到其靶基因(IRF1(?)CyclinD1)的3’非编码区而提高miR-383诱导的细胞增殖抑制效应。另一方面,在NT-2和GC1(小鼠精原细胞系)中,FMRP的水平也被miR-383直接靶向Cyclin D1而下调。在Fmr1基因敲除小鼠睾丸中,我们发现miR-383表达下调、CDK4表达定位失调、DNA损伤增加等现象,而相似的现象在FMRP下调的MA型男性不育患者的睾丸中也被检测到。因而,FMRP-miR-383在精子发生中可以构成一个潜在的反馈调控回路,FMRP则扮演miR-383功能的负调因子角色。我们的研究成果也表明FMRP-miR-383调控通路的失调可能和MA型男性不育的发生密切相关。
另一方面,遗传因素也能影响男性不育。Kallmann综合症(KS)是一个遗传性进行性的失调疾病,症状为低促性腺激素功能减退症(导致不育)和嗅觉缺失／降低。由于在胚胎期的嗅球发育不全,神经内分泌细胞GnRH不能正常的沿着嗅神经纤维从鼻部向前脑迁移。现在已经发现大量的基因均与这种神经元的轴突导向相关,KS也被发现是一种遗传异质性疾病,涉及到多种遗传方式。但是,如今已经发现的致病基因只能解释近三分之一的KS患者的病因,还远远不能完全解释这种疾病,提示了还存在其他基因或调控通路参与到KS的发生中。在本论文的第三部分中,我们报道了一个汉族母系遗传KS家系。这个家系存在两个新发协同突变,分别是KAL1基因146G>T突变(p.49Cys>Phe)线粒体tRNAcysmt.5800A>G突变。进一步,线粒体cysteinyl-tRNA途径的失调能显著影响GnRH神经元细胞的体外迁移。而且,线粒体cysteinyl-tRNA转移酶Cars2基因也是调控斑马鱼GnRH3神经元迁移、幼鱼存活和斑马鱼嗅觉功能的关键因素。因此,在这部分我们提出了线粒体在GnRH(?)神经元迁移中起到重要的作用,为KS的遗传病因学提供了新的线索。
综上所述,本论文研究结果阐述了miR-383/FMRP反馈调控回路在精原细胞增殖凋亡调控和KAL1/线粒体半胱氨酸tRNA途径在Kallmann综合症中的功能。这些研究成果将为进一步理解精子发生缺陷和GnRH神经元迁移异常的分子调控机制奠定基础。
Infertility affects10-15%of couples who are trying to conceive, and half of the cases are due to male factors. Despite several decades of efforts to elucidate the etiologic mechanism of male infertility, most cases are idiopathic. For example, a significant proportion of male infertility is diagnosed as unexplained non-obstructive azoospermia (NOA). Furthermore, patients with NOA usually had a significantly lo-wer sperm retrieval rate and a clinical pregnancy rate. Therefore, elucidating the underlying molecular pathogenesis of NOA may help to improve treatment outcomes and therpies in these patients.
Spermatogenesis is a tightly regulated process during which spermatogonial stem cells develop into highly differentiated spermatozoa. The meiotic and haploid phases of spermatogenesis are characterized by high transcriptional activity but repressed translational activity. Translational repression of mRNAs in these phases must be achieved through a posttranscriptional regulatory mechanism, one of which is mediated by microRNAs (miRNAs). Our group had reported that miRNA-383expression is down-regulated in the testes of infertile men with maturation arrest (MA). So the first aim of this study was to understand the underlying mechanisms of miR-383involved in the pathogenesis of MA. miR-383targeted a tumor suppressor, interferon regulatory factor-1(IRF1), which in turn resulted in suppression of proliferation, cell-cycle arrest in G1phase and induction of apoptosis, a reduction of Cyclin D1, CDK2and p21levels, and an inhibition of pRb phosphorylation. These results suggest that miR-383functions as a negative regulator of proliferation by targeting IRF-1, in part, through inactivation of the pRb pathway. Abnormal testicular miR-383expression may potentiate the connections between male infertility and testicular germ cell tumor.
Although miR-383was expression is downregulated in the testes of infertile men with MA, how miR-383's functions and targeting were regulated in spermatogenesis still remained unknow. So in the second part of this study (Chapter Three), we were trying to elucilate the regulating mechanisms of miR-383during spermatogenesis. We found that FMRP was associated with88miRNAs in mouse testis including miR-383. FMRP enhanced miR-383-induced suppression of cell proliferation by decreasing the interaction between FMRP and miR-383and then affecting miR-383binding to the3'UTR of its target genes IRF1and Cyclin Dl. Furthermore, FMRP levels were also down-regulated by miR-383by targeting Cyclin D1directly. Reduced miR-383 expression, dysregulated CDK4expression and increased DNA damage were also observed in the testes of Fmrl knockout mice and of MA patients with a down-regulation of FMRP. A potential feedback loop between FMRP and miR-383during spermatogenesis is proposed, and FMRP acts as a negative regulator of miR-383functions. Our data also indicate that dysregulation of the FMRP-miR-383pathway may partially contribute to human spermatogenic failure with MA.
On the other hand, genetic factor also can affect male infertility. Kallmann syndrome (KS) is an inherited developmental disorder defined as the association of hypogonadotropic hypogonadism (causing male infertility) and anosmia or hyposmia. Due to olfactory bulb agenesis during embryonic development, the neuroendocrine GnRH cells fail to migrate from the nose to the forebrain along the olfactory nerve fibers.Various genes are involved the axonal pathfinding of the neurons, and KS has been shown to be a genetically heterogeneous disease with different modes of inheritance. However, mutations in any of the causative genes identified so far are only found in approximately one third of KS patients, thus indicating that other genes or pathways remain to be discovered. In the third part of this study, we report a large Han Chinese family with maternally inherited KS. The synergistic effect of mutations in KAL1(146G>T (p.49Cys>Phe))and mitochondrial tRNAcys(mt.5800A>G) can account for the occurrence of the disorder in this family. Furthermore, the disturbance of the mitochondrial cysteinyl-tRN A pathway can significantly influence the migration of GnRH cells in vitro. Also, Cars2is essential for the migration of GnRH3neurons, survival of larvae and sense of smell in zebrafish. Therefore, we propose that the mitochondria play important roles in the migration of GnRH cells and provide valuable clues to the genetic etiology of KS.
In summary, the results in this study revealed the role of miR-383/FMRP feedback pathway in control of spermatogonial proliferation and apoptosis, and mitochondrial cysteinyl-tRNA pathway in Kallmann syndrome. These results could help to further understanding of the underlying mechanisms of spermatogenesis failure and defects in GnRH nueron development in NO A and KS patients.
引文
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