胰岛素和胰岛素样生长因子(IGFs)在代谢和生长中的作用早为人们所知，近日科学家们发现了它们在另一个舞台——性别决定中的重要作用。来自日内瓦大学的研究人员证实在决定性别的关键时刻缺乏这些因子，胚胎不能分化为男性或女性，且不会形成肾上腺。这一研究发现发布在《PLOS Genetics》杂志上。
在哺乳动物中，精子赋予的X或Y染色体决定了胚胎的遗传性别，随后的发育阶段这一遗传性别差异被转变为生殖腺性别差异，男女分别发育出卵巢及睾丸不同的生殖器。研究人员希望更好地了解性发育的第一阶段。
尽管已知胰岛素和IGFs参与调控了代谢、生长和生殖能力之间的相互作用，新研究表明这些相互作用远比以往认为的更为重要，研究人员证实胰岛素和IGF受体还是哺乳动物初期性别决定的必要条件。
为了分析这些激素对于性别决定的影响，研究小组利用转基因小鼠开展了研究。科学家们证实遗传失活小鼠胚胎中的胰岛素和IGFs受体，可导致性别决定前XX和XY性腺中的祖细胞增殖率下降，成百上千与肾上腺、睾丸和卵巢遗传程序相关的基因下调。由此导致胚胎和性腺数日均停留在一种完全未分化的状态。
研究人员发现，缺失功能性胰岛素/ IGF信号的胚胎显示出肾上腺皮质发育不全，胚胎XY性腺性逆转，Sry上调延迟，及随后睾丸遗传程序故障，卵巢分化延迟，在胚胎16.5天卵巢分化程序最终启动前，突变性腺仍维持在一种持久的未分化状态。研究结果表明这些激素和生长因子在性分化中起至关重要的作用。
日内瓦大学遗传医学和发育系教授Serge Nef说：“本研究有助于更深入地探索性发育基础机制，朝着更好地了解性别不明的原因迈出了重要的一步。我们正在开展的研究将为改善提高性发育异常个体的临床诊断提供新机遇。(生物谷Bioon.com)
doi:10.1371/journal.pgen.1003160.g008
PMC:
PMID:
Insulin and IGF1 Receptors Are Essential for XX and XY Gonadal Differentiation and Adrenal Development in Mice
Jean-Luc Pitetti Pierre Calvel Yannick Romero, Béatrice Conne, Vy Truong, Marilena D. Papaioannou, Olivier Schaad, Mylène Docquier, Pedro Luis Herrera, Dagmar Wilhelm, Serge Nef mail
Mouse sex determination provides an attractive model to study how regulatory genetic networks and signaling pathways control cell specification and cell fate decisions. This study characterizes in detail the essential role played by the insulin receptor (INSR) and the IGF type I receptor (IGF1R) in adrenogenital development and primary sex determination. Constitutive ablation of insulin/IGF signaling pathway led to reduced proliferation rate of somatic progenitor cells in both XX and XY gonads prior to sex determination together with the downregulation of hundreds of genes associated with the adrenal, testicular, and ovarian genetic programs. These findings indicate that prior to sex determination somatic progenitors in Insr;Igf1r mutant gonads are not lineage primed and thus incapable of upregulating/repressing the male and female genetic programs required for cell fate restriction. In consequence, embryos lacking functional insulin/IGF signaling exhibit (i) complete agenesis of the adrenal cortex, (ii) embryonic XY gonadal sex reversal, with a delay of Sry upregulation and the subsequent failure of the testicular genetic program, and (iii) a delay in ovarian differentiation so that Insr;Igf1r mutant gonads, irrespective of genetic sex, remained in an extended undifferentiated state, before the ovarian differentiation program ultimately is initiated at around E16.5.
