胰島素和胰島素樣生長(zhǎng)因子(IGFs)在代謝和生長(zhǎng)中的作用早為人們所知,，近日科學(xué)家們發(fā)現(xiàn)了它們?cè)诹硪粋€(gè)舞臺(tái)——性別決定中的重要作用,。來自日內(nèi)瓦大學(xué)的研究人員證實(shí)在決定性別的關(guān)鍵時(shí)刻缺乏這些因子，胚胎不能分化為男性或女性,，且不會(huì)形成腎上腺,。這一研究發(fā)現(xiàn)發(fā)布在《PLOS Genetics》雜志上。
在哺乳動(dòng)物中,，精子賦予的X或Y染色體決定了胚胎的遺傳性別,，隨后的發(fā)育階段這一遺傳性別差異被轉(zhuǎn)變?yōu)樯诚傩詣e差異，男女分別發(fā)育出卵巢及睪丸不同的生殖器,。研究人員希望更好地了解性發(fā)育的第一階段,。
盡管已知胰島素和IGFs參與調(diào)控了代謝、生長(zhǎng)和生殖能力之間的相互作用,，新研究表明這些相互作用遠(yuǎn)比以往認(rèn)為的更為重要,，研究人員證實(shí)胰島素和IGF受體還是哺乳動(dòng)物初期性別決定的必要條件。
為了分析這些激素對(duì)于性別決定的影響,，研究小組利用轉(zhuǎn)基因小鼠開展了研究,。科學(xué)家們證實(shí)遺傳失活小鼠胚胎中的胰島素和IGFs受體,，可導(dǎo)致性別決定前XX和XY性腺中的祖細(xì)胞增殖率下降,，成百上千與腎上腺、睪丸和卵巢遺傳程序相關(guān)的基因下調(diào),。由此導(dǎo)致胚胎和性腺數(shù)日均停留在一種完全未分化的狀態(tài),。
研究人員發(fā)現(xiàn)，缺失功能性胰島素/ IGF信號(hào)的胚胎顯示出腎上腺皮質(zhì)發(fā)育不全,，胚胎XY性腺性逆轉(zhuǎn),，Sry上調(diào)延遲，及隨后睪丸遺傳程序故障,，卵巢分化延遲,，在胚胎16.5天卵巢分化程序最終啟動(dòng)前，突變性腺仍維持在一種持久的未分化狀態(tài)。研究結(jié)果表明這些激素和生長(zhǎng)因子在性分化中起至關(guān)重要的作用,。
日內(nèi)瓦大學(xué)遺傳醫(yī)學(xué)和發(fā)育系教授Serge Nef說：“本研究有助于更深入地探索性發(fā)育基礎(chǔ)機(jī)制,，朝著更好地了解性別不明的原因邁出了重要的一步。我們正在開展的研究將為改善提高性發(fā)育異常個(gè)體的臨床診斷提供新機(jī)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.
