两篇Cell子刊揭示性别决定机制

德国Mainz大学分子生物学研究所的科学家，确定了启动雄性性器官发育所必须的蛋白。英国Andy Greenfield研究组也在同期Developmental Cell发表了类似的研究成果，两篇文章共同揭示了一个控制胚胎性别发育的基因网络。

　　

生物通报道：德国Mainz大学分子生物学研究所的科学家，确定了启动雄性性器官发育所必须的蛋白。研究显示，缺乏Gadd45g基因会导致雄性小鼠性别完全反转，使它们长得像雌性小鼠一样，文章发表在Cell旗下Developmental Cell杂志上。英国Andy Greenfield研究组也在同期Developmental Cell发表了类似的研究成果，两篇文章共同揭示了一个控制胚胎性别发育的基因网络。

由德国Mainz大学Christof Niehrs教授领导的研究显示，仅删除一个基因Gadd45g，就会使雄性小鼠长出与雌性小鼠相差无几的外生殖器。此外，Gadd45g突变型小鼠的内部生殖器也与雌性小鼠很相似，Gadd45g突变使雄性小鼠发生了完全的性别反转。Christof Niehrs介绍说，“在培养Gadd45g突变型小鼠时得到的都是雌性，这使我们很疑惑，直到我们发现这些雌性小鼠中有些实际上携带有Y染色体。”

研究人员进一步发现，Gadd45g是通过调节控制着Sry基因的信号级联发挥功能，此前有研究显示Sry是雄性性别发育的主要调节子。这项研究不仅发现了Gadd45g的新功能，也揭示了控制性别发育的新信号通路，对于性别发育类疾病研究有重要启示。

在胚胎发育过程中，雄性器官要正确发育，Sry基因就必须在特定时间段以高水平表达。而研究人员发现，Gadd45g的表达模式与Sry高度相似。只不过Gadd45g 基因比Sry稍早一点启动。此外，在缺乏Gadd45g基因的小鼠体内，Sry基因不能正确表达，说明Gadd45g通过调控雄性发育的主要调节子，来影响雄性小鼠的发育。

文章还描述了Gadd45g调控Sry 的潜在机制，这一机制指出，Gadd45g结合并激活关键的信号蛋白（如p38），随后这些信号蛋白激活转录因子Gata4。转录因子被激活后，会与Sry基因结合并使之启动。

英国Andy Greenfield研究组也在同期Developmental Cell发表了类似研究成果。他们的研究指出，MAP3K4激酶或Gadd45缺乏都会导致小鼠发生性别反转，而Gadd45与Map3k4在性别决定中存在相互作用，Map3k4过表达可以抵消Gadd45缺失。在上述两种突变中，性别反转都与p38 MAPK和GATA4的磷酸化有关。研究人员指出，GADD45与MAP3K4相互作用是通过p38 MAPK控制Sry基因的表达，并由此控制小鼠性别发育的。

（生物通编辑：叶予）

生物通推荐原文摘要：

GADD45G Functions in Male Sex Determination by Promoting p38 Signaling and Sry Expression

Male sex determination in mammals is induced by Sry, a gene whose regulation is poorly understood. Here we show that mice mutant for the stress-response gene Gadd45g display complete male-to-female sex reversal. Gadd45g and Sry have a strikingly similar expression pattern in the genital ridge, and they are coexpressed in gonadal somatic cells. In Gadd45g mutants, Sry expression is delayed and reduced, and yet Sry seemed to remain poised for expression, because its promoter is demethylated on schedule and is occupied by active histone marks. Instead, p38 MAPK signaling is impaired in Gadd45g mutants. Moreover, the transcription factor GATA4, which is required for Sry expression, binds to the Sry promoter in vivo in a MAPK-dependent manner. The results suggest that a signaling cascade, involving GADD45G p38 MAPK GATA4 SRY, regulates male sex determination.

Gadd45 and Map3k4 Interactions Regulate Mouse Testis Determination via p38 MAPK-Mediated Control of Sry Expression

Loss of the kinase MAP3K4 causes mouse embryonic gonadal sex reversal due to reduced expression of the testis-determining gene, Sry. However, because of widespread expression of MAP3K4, the cellular basis of this misregulation was unclear. Here, we show that mice lacking Gadd45 also exhibit XY gonadal sex reversal caused by disruption to Sry expression. Gadd45 is expressed in a dynamic fashion in somatic cells of the developing gonads from 10.5 days postcoitum (dpc) to 12.5 dpc. Gadd45 and Map3k4 genetically interact during sex determination, and transgenic overexpression of Map3k4 rescues gonadal defects in Gadd45-deficient embryos. Sex reversal in both mutants is associated with reduced phosphorylation of p38 MAPK and GATA4. In addition, embryos lacking both p38α and p38β also exhibit XY gonadal sex reversal. Taken together, our data suggest a requirement for GADD45 in promoting MAP3K4-mediated activation of p38 MAPK signaling in embryonic gonadal somatic cells for testis determination in the mouse.