Krausz Csilla, Sassone-Corsi Paolo
Andrology Unit, Department of Clinical Physiopathology, University of Florence, Viale Pieraccini, 6, Florence 50139, Italy.
Reprod Biomed Online. 2005 Jan;10(1):64-71. doi: 10.1016/s1472-6483(10)60805-x.
Male germ cell differentiation requires a highly cell-specific gene expression programme that is achieved by unique chromatin remodelling, transcriptional control, and the expression of testis-specific genes or isoforms. The regulatory processes governing gene expression in spermatogenesis have fundamentally unique requirements, including meiosis, ongoing cellular differentiation and a peculiar chromatin organization. The signalling cascades and the downstream effectors contributing to the programme of spermatogenesis are currently being unravelled, revealing the unique features of germ cell regulatory circuits. This paper reports on the unique role that CREM exerts as a master regulator. Targeted inactivation of the genes encoding CREM and ACT has been achieved. ACT selectively associates with KIF17b, a kinesin motor protein highly expressed in germ cells. It has been found that KIF17b directly determines the intracellular localization of ACT. Thus, the activity of a transcriptional co-activator is intimately coupled to the function of a kinesin via tight regulation of its intracellular localization. The conservation of these elements and of their regulatory functions in human spermatogenesis indicates that they are likely to provide important insights into understanding the molecular mechanisms of human infertility.
雄性生殖细胞分化需要高度细胞特异性的基因表达程序，这通过独特的染色质重塑、转录控制以及睾丸特异性基因或异构体的表达来实现。精子发生过程中控制基因表达的调控过程具有根本上独特的要求，包括减数分裂、持续的细胞分化以及特殊的染色质组织。目前正在揭示参与精子发生程序的信号级联和下游效应器，从而揭示生殖细胞调控回路的独特特征。本文报道了CREM作为主要调节因子所发挥的独特作用。已经实现了对编码CREM和ACT的基因的靶向失活。ACT选择性地与KIF17b结合，KIF17b是一种在生殖细胞中高度表达的驱动蛋白运动蛋白。已经发现KIF17b直接决定ACT的细胞内定位。因此，转录共激活因子的活性通过对其细胞内定位的严格调控与驱动蛋白的功能紧密耦合。这些元件及其调控功能在人类精子发生中的保守性表明，它们可能为理解人类不育的分子机制提供重要见解。
