Gesina E, Blondeau B, Milet A, Le Nin I, Duchene B, Czernichow P, Scharfmann R, Tronche F, Breant B
INSERM U690, Hospital Robert Debré, Paris, France.
Diabetologia. 2006 Dec;49(12):2939-47. doi: 10.1007/s00125-006-0449-3. Epub 2006 Sep 26.
AIMS/HYPOTHESIS: Beta cell development is sensitive to glucocorticoid levels. Although direct effects of glucocorticoids on pancreatic precursors have been shown to control beta cell mass expansion, indirect effects of these hormones on pancreatic development remain unexplored. This issue was addressed in mice lacking the glucocorticoid receptor (GR) in the whole organism.
The pancreatic phenotype of GR(null/null) mice was studied at fetal ages (embryonic day [E]) E15.5 and E18 by immunohistochemistry and beta cell fraction measurements. To distinguish between direct and indirect effects, mutant E15.5 fetal pancreata were grafted under the kidney capsule of immunodeficient mice and analysed after 1 week.
E18 GR(null/null) fetuses had smaller digestive tracts and tiny pancreata. Massive pancreatic disorganisation and apoptosis were observed despite the presence of all cell types. E15.5 GR(null/null) mutants were indistinguishable from wild-type regarding pancreatic size, tissue structure and organisation, beta cell fraction and production of exocrine transcription factor Ptf1a, neurogenin 3 and Pdx-1. Grafting E15.5 GR(null/null) pancreata into a GR-expressing environment rescued the increased apoptosis and mature islets were observed, suggesting that GR(null/null) pancreatic cell death can be attributed to indirect effects of glucocorticoids on this tissue. Heterozygous GR(+/null) mutants with reduced GR numbers showed no apoptosis but increased beta cell fraction at E18 and the adult age, strengthening the importance of an accurate GR dosage on beta cell mass expansion.
CONCLUSIONS/INTERPRETATION: Our results provide evidence for GR involvement in pancreatic tissue organisation and survival through indirect effects. GR does not appear necessary for early phases, but its accurate dosage is critical to modulate beta cell mass expansion at later fetal stages, presumably through direct effects.
目的/假设：β细胞发育对糖皮质激素水平敏感。虽然已证明糖皮质激素对胰腺前体细胞的直接作用可控制β细胞量的增加，但其对胰腺发育的间接作用仍未得到探索。本研究在全身缺乏糖皮质激素受体（GR）的小鼠中探讨了这一问题。
通过免疫组织化学和β细胞比例测量，研究GR（纯合缺失/null/null）小鼠在胎龄（胚胎日[E]）E15.5和E18时的胰腺表型。为区分直接和间接作用，将E15.5突变型胎儿胰腺移植到免疫缺陷小鼠的肾包膜下，并在1周后进行分析。
E18的GR（纯合缺失/null/null）胎儿消化道较小，胰腺微小。尽管存在所有细胞类型，但仍观察到大量胰腺结构紊乱和细胞凋亡。E15.5的GR（纯合缺失/null/null）突变体在胰腺大小、组织结构、β细胞比例以及外分泌转录因子Ptf1a、神经生成素3和Pdx-1的产生方面与野生型无差异。将E15.5的GR（纯合缺失/null/null）胰腺移植到表达GR的环境中可挽救增加的细胞凋亡，并观察到成熟胰岛，这表明GR（纯合缺失/null/null）胰腺细胞死亡可归因于糖皮质激素对该组织的间接作用。GR数量减少的杂合子GR（+/null）突变体在E18和成年期未出现细胞凋亡，但β细胞比例增加，这进一步证明了准确的GR剂量对β细胞量增加的重要性。
结论/解读：我们的数据为GR通过间接作用参与胰腺组织的形成和存活提供了证据。GR在早期阶段似乎并非必需，但准确的剂量对于调节胎儿后期β细胞量的增加至关重要，可能是通过直接作用实现的。
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