近日來自澳大利亞研究人員的新研究成果朝揭示人類性發(fā)育的奧秘又邁進了一步，在一系列的遺傳學(xué)研究中科研人員通過激活一個古老的大腦基因生成了無Y染色體的雄性小鼠。研究論文在線發(fā)表在《臨床研究雜志》 Journal of Clinical Investigation上。
雄性生物的體細胞中通常包含一條Y染色體和一條X染色體,，而雌性生物的體細胞中則包含兩條X染色體,。過去的研究證實Y染色體上的SRY基因可啟動早期胚胎的睪丸發(fā)育,，一旦睪丸開始形成,，胚胎的其余部分也隨之轉(zhuǎn)變?yōu)樾坌浴Ｔ谛卵芯恐?，研究人員找到了一種新方法通過激活發(fā)育胚胎中的SOX3基因生成了無Y染色體的雄性小鼠,。SOX3是已知的與大腦發(fā)育相關(guān)的重要因子，之前一直未有研究證實SOX3能夠夠啟動雄性信號通路。
“Y染色體上包含的SRY基因是胚胎發(fā)育過程中激活雄性信號通路的一個基因開關(guān),，”澳大利亞阿德萊德分子與生物醫(yī)學(xué)科學(xué)院的副教授Paul Thomas說：“SRY基因僅存在于哺乳動物中,，研究人員質(zhì)疑它有可能是在早期哺乳動物進化中從SOX3基因進化而來。”
Thomas和同事們通過在發(fā)育性腺中激活SOX3基因的方法生成了帶有兩條X染色體的雄性小鼠,。“這些XX雄性‘性別逆轉(zhuǎn)’小鼠在外表,、生殖結(jié)構(gòu)和行為上完全表現(xiàn)為雄性,，但是由于不能生成精子因而導(dǎo)致不育,，”Thomas說：“長期以來我們都懷疑SOX3是SRY基因的進化前體基因。在研究中我們證實SOX3能夠以與SRY相同的方式激活雄性信號通路,，從而驗證了我們之前的猜測,。”
這項研究工作是Thomas與英國醫(yī)學(xué)研究委員會國家醫(yī)學(xué)研究所的Robin Lovell-Badge博士協(xié)作完成。20年前Robin Lovell-Badge在小鼠中發(fā)現(xiàn)了SRY基因,。Lovell-Badge博士說：“我對此研究發(fā)現(xiàn)感到非常興奮,。過去的研究證實SOX3在神經(jīng)系統(tǒng)發(fā)育中發(fā)揮作用。我們的新研究發(fā)現(xiàn)在早期性腺中SOX3的一個突變可以使其激活,，從而促使睪丸發(fā)育,。”
“通過研究這些XX雄性小鼠和人類可能存在一些相似之處，我們或許能夠揭示我們早期的哺乳動物祖先的進化過程,，發(fā)現(xiàn)X染色體和Y染色體的進化機制,，”Lovell-Badge說。
目前Thomas等在與默多克兒童研究所的Andrew Sinclair教授和加州大學(xué)洛杉磯分校的Eric Vilain教授的進一步合作研究中已經(jīng)證實人類某些XX男性存在有SOX3基因的改變,。（生物谷Bioon.com）
生物谷推薦原文出處：
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.
