近日来自澳大利亚研究人员的新研究成果朝揭示人类性发育的奥秘又迈进了一步，在一系列的遗传学研究中科研人员通过激活一个古老的大脑基因生成了无Y染色体的雄性小鼠。研究论文在线发表在《临床研究杂志》 Journal of Clinical Investigation上。
雄性生物的体细胞中通常包含一条Y染色体和一条X染色体，而雌性生物的体细胞中则包含两条X染色体。过去的研究证实Y染色体上的SRY基因可启动早期胚胎的睾丸发育，一旦睾丸开始形成，胚胎的其余部分也随之转变为雄性。在新研究中，研究人员找到了一种新方法通过激活发育胚胎中的SOX3基因生成了无Y染色体的雄性小鼠。SOX3是已知的与大脑发育相关的重要因子，之前一直未有研究证实SOX3能够够启动雄性信号通路。
“Y染色体上包含的SRY基因是胚胎发育过程中激活雄性信号通路的一个基因开关，”澳大利亚阿德莱德分子与生物医学科学院的副教授Paul Thomas说：“SRY基因仅存在于哺乳动物中，研究人员质疑它有可能是在早期哺乳动物进化中从SOX3基因进化而来。”
Thomas和同事们通过在发育性腺中激活SOX3基因的方法生成了带有两条X染色体的雄性小鼠。“这些XX雄性‘性别逆转’小鼠在外表、生殖结构和行为上完全表现为雄性，但是由于不能生成精子因而导致不育，”Thomas说：“长期以来我们都怀疑SOX3是SRY基因的进化前体基因。在研究中我们证实SOX3能够以与SRY相同的方式激活雄性信号通路，从而验证了我们之前的猜测。”
这项研究工作是Thomas与英国医学研究委员会国家医学研究所的Robin Lovell-Badge博士协作完成。20年前Robin Lovell-Badge在小鼠中发现了SRY基因。Lovell-Badge博士说：“我对此研究发现感到非常兴奋。过去的研究证实SOX3在神经系统发育中发挥作用。我们的新研究发现在早期性腺中SOX3的一个突变可以使其激活，从而促使睾丸发育。”
“通过研究这些XX雄性小鼠和人类可能存在一些相似之处，我们或许能够揭示我们早期的哺乳动物祖先的进化过程，发现X染色体和Y染色体的进化机制，”Lovell-Badge说。
目前Thomas等在与默多克儿童研究所的Andrew Sinclair教授和加州大学洛杉矶分校的Eric Vilain教授的进一步合作研究中已经证实人类某些XX男性存在有SOX3基因的改变。（生物谷Bioon.com）
生物谷推荐原文出处：
J Clin Invest. doi:10.1172/JCI42580.
Identification of SOX3 as an XX male sex reversal gene in mice and humans
Edwina Sutton1, James Hughes1, Stefan White2, Ryohei Sekido3, Jacqueline Tan2, Valerie Arboleda4, Nicholas Rogers1, Kevin Knower5, Lynn Rowley2, Helen Eyre6, Karine Rizzoti3, Dale McAninch1, Joao Goncalves7, Jennie Slee8, Erin Turbitt2, Damien Bruno2, Henrik Bengtsson9, Vincent Harley5, Eric Vilain4, Andrew Sinclair2, Robin Lovell-Badge3 and Paul Thomas1
1School of Molecular and Biomedical Science and Australian Research Council Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, South Australia, Australia.
2Murdoch Children’s Research Institute and Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Melbourne, Victoria, Australia.
3Division of Developmental Genetics, MRC National Institute for Medical Research, London, United Kingdom.
4Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California USA.
5Prince Henry’s Institute of Medical Research, Melbourne, Victoria, Australia.
6Women’s and Children’s Hospital, North Adelaide, South Australia, Australia.
7Centro de Genética Humana, Instituto Nacional de Saúde Dr Ricardo Jorge, Lisbon, Portugal.
8Genetic Services of Western Australia, King Edward Memorial Hospital, Subiaco, Western Australia, Australia.
9Department of Statistics, University of California, Berkeley, California, USA.
Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and XX females). The Y chromosome–linked gene sex-determining region Y (SRY) is believed to be the master initiator of male sex determination in almost all eutherian and metatherian mammals, functioning to upregulate expression of its direct target gene Sry-related HMG box–containing gene 9 (SOX9). Data suggest that SRY evolved from SOX3, although there is no direct functional evidence to support this hypothesis. Indeed, loss-of-function mutations in SOX3 do not affect sex determination in mice or humans. To further investigate Sox3 function in vivo, we generated transgenic mice overexpressing Sox3. Here, we report that in one of these transgenic lines, Sox3 was ectopically expressed in the bipotential gonad and that this led to frequent complete XX male sex reversal. Further analysis indicated that Sox3 induced testis differentiation in this particular line of mice by upregulating expression of Sox9 via a similar mechanism to Sry. Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal. Together, these data suggest that SOX3 and SRY are functionally interchangeable in sex determination and support the notion that SRY evolved from SOX3 via a regulatory mutation that led to its de novo expression in the early gonad.
