Infertility with Defective Spermiogenesis in Mice Lacking AF5q31, the Target of Chromosomal Translocation in Human Infant Leukemia
Infertility with Defective Spermiogenesis in Mice Lacking AF5q31, the Target of Chromosomal Translocation in Human Infant Leukemia
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DOI：
10.1128/mcb.25.15.6834-6845.2005
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发表时间：
2005-08
影响因子：
5.3
通讯作者：
Atsushi Urano;M. Endoh;T. Wada;Y. Morikawa;M. Itoh;Y. Kataoka;T. Taki;H. Akazawa;H. Nakajima;I. Komuro;N. Yoshida;Y. Hayashi;H. Handa;T. Kitamura;T. Nosaka
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作者：
Atsushi Urano;M. Endoh;T. Wada;Y. Morikawa;M. Itoh;Y. Kataoka;T. Taki;H. Akazawa;H. Nakajima;I. Komuro;N. Yoshida;Y. Hayashi;H. Handa;T. Kitamura;T. Nosaka
AF5q31(又称MCEF)与婴儿急性淋巴细胞白血病相关的MLL基因参与染色体易位而被鉴定。已经提出了AF5q31和其他家族基因的几个潜在作用，但AF5q31在发育过程中的具体要求仍然不清楚。在这里，我们证明了AF5q31是精子发生所必需的。虽然大多数AF5q31缺陷小鼠在子宫和新生儿时死亡，胚胎发育受损和肺泡缩小，但13%的AF5q31缺陷小鼠像野生型小鼠一样茁壮成长。然而，雄性小鼠是无精子症不育小鼠。组织学检查显示精子发生阶段生殖细胞发育受阻，附睾内几乎看不到精子。AF5q31在Sertoli细胞中优先表达。此外，突变小鼠表现出鱼精蛋白1、鱼精蛋白2和过渡蛋白2的表达严重受损，这是紧凑精子头内单倍体基因组所必需的，并增加了生精小管中的凋亡细胞。因此，AF5q31似乎在睾丸体细胞中发挥转录调节作用，对雄性生殖细胞的分化和生存是必不可少的。这些结果可能对理解人类男性不育有临床意义。
ABSTRACT AF5q31 (also called MCEF) was identified by its involvement in chromosomal translocation with the gene MLL (mixed lineage leukemia), which is associated with infant acute lymphoblastic leukemia. Several potential roles have been proposed for AF5q31 and other family genes, but the specific requirements of AF5q31 during development remain unclear. Here, we show that AF5q31 is essential for spermatogenesis. Although most AF5q31-deficient mice died in utero and neonatally with impaired embryonic development and shrunken alveoli, respectively, 13% of AF5q31-deficient mice thrived as wild-type mice did. However, the male mice were sterile with azoospermia. Histological examinations revealed the arrest of germ cell development at the stage of spermiogenesis, and virtually no spermatozoa were seen in the epididymis. AF5q31 was found to be preferentially expressed in Sertoli cells. Furthermore, mutant mice displayed severely impaired expression of protamine 1, protamine 2, and transition protein 2, which are indispensable to compact the haploid genome within the sperm head, and an increase of apoptotic cells in seminiferous tubules. Thus, AF5q31 seems to function as a transcriptional regulator in testicular somatic cells and is essential for male germ cell differentiation and survival. These results may have clinical implications in the understanding of human male infertility.