Knockout of insulin-like growth factor-1 receptor impairs distal lung morphogenesis.
Knockout of insulin-like growth factor-1 receptor impairs distal lung morphogenesis.
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DOI：
10.1371/journal.pone.0048071
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Holzenberger M
中科院分区：
文献类型：
--
作者：
Epaud R;Aubey F;Xu J;Chaker Z;Clemessy M;Dautin A;Ahamed K;Bonora M;Hoyeau N;Fléjou JF;Mailleux A;Clement A;Henrion-Caude A;Holzenberger M
胰岛素样生长因子（IGF-I和IGF-II）是脊椎动物体细胞生长和发育的多效性调节因子。这两种激素的内分泌和旁分泌作用由共同的IGF 1型受体（IGF-1 R）介导。新生儿IGF-1 R基因敲除小鼠的致命性呼吸衰竭表明这种受体在肺发育中的特殊作用，因此我们研究了肺组织中IGF-1 R失活的后果。我们首先产生了复合杂合子突变小鼠，它们携带一个亚型（Igf 1 rneo）和一个无效（Igf 1 r −）等位基因。这些IGF-1 Rneo/−小鼠仅表达正常IGF-1 R水平的22%，并且是可行的。在成年IGF-1 Rneo/−小鼠中，我们评估了肺形态和呼吸生理学，发现正常的组织形态特征和对高碳酸血症的正常呼吸反应。然后，我们产生了纯合子IGF-1 R敲除突变体（IGF-1 R −/−），并使用组织形态计量学和免疫组织化学方法分析了它们在妊娠晚期的肺发育。IGF-1 R −/−胚胎表现出严重的肺发育不全和明显不发达的横膈膜，导致致命的新生儿呼吸窘迫。重要的是，来自妊娠晚期胚胎的IGF-1 R −/−肺比对照肺小四倍，并且显示出明显增厚的囊间充质，表明肺成熟严重延迟。与IGF-1 R +/+对照组相比，IGF-1 R −/−肺组织中的细胞增殖和凋亡显著增加。使用pro-SP-C，NKX 2 -1，CD 31和vWF作为标记物的免疫组织化学显示，在IGF-1 R −/−突变小鼠中，细胞分化延迟，并在产前呼吸器官发育的小管阶段停滞。我们发现低水平的IGF-1 R足以确保小鼠正常的肺部发育。相反，IGF-1 R的完全缺失显著延迟了妊娠末期肺成熟。结果表明，IGF-1 R在胎儿肺发育过程中的细胞增殖和细胞分化的时间起着至关重要的作用。
Insulin-like growth factors (IGF-I and -II) are pleiotropic regulators of somatic growth and development in vertebrate species. Endocrine and paracrine effects of both hormones are mediated by a common IGF type 1 receptor (IGF-1R). Lethal respiratory failure in neonatal IGF-1R knockout mice suggested a particular role for this receptor in pulmonary development, and we therefore investigated the consequences of IGF-1R inactivation in lung tissue. We first generated compound heterozygous mutant mice harboring a hypomorphic (Igf1rneo) and a null (Igf1r−) allele. These IGF-1Rneo/− mice express only 22% of normal IGF-1R levels and are viable. In adult IGF-1Rneo/− mice, we assessed lung morphology and respiratory physiology and found normal histomorphometric characteristics and normal breathing response to hypercapnia. We then generated homozygous IGF-1R knockout mutants (IGF-1R−/−) and analyzed their lung development during late gestation using histomorphometric and immunohistochemical methods. IGF-1R−/− embryos displayed severe lung hypoplasia and markedly underdeveloped diaphragms, leading to lethal neonatal respiratory distress. Importantly, IGF-1R−/− lungs from late gestation embryos were four times smaller than control lungs and showed markedly thickened intersaccular mesenchyme, indicating strongly delayed lung maturation. Cell proliferation and apoptosis were significantly increased in IGF-1R−/− lung tissue as compared with IGF-1R+/+ controls. Immunohistochemistry using pro-SP-C, NKX2-1, CD31 and vWF as markers revealed a delay in cell differentiation and arrest in the canalicular stage of prenatal respiratory organ development in IGF-1R−/− mutant mice. We found that low levels of IGF-1R were sufficient to ensure normal lung development in mice. In contrast, complete absence of IGF-1R significantly delayed end-gestational lung maturation. Results indicate that IGF-1R plays essential roles in cell proliferation and timing of cell differentiation during fetal lung development.
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影响因子：
10.5
作者：
POWELLBRAXTON, L;HOLLINGSHEAD, P;STEWART, TA
通讯作者：
STEWART, TA
影响因子：
4.8
作者：
Silva, Delia;Venihaki, Maria;Lopez, Mary Frances
通讯作者：
Lopez, Mary Frances
影响因子：
3.6
作者：
Bonora, M;Bernaudin, JF;Brahimi-Horn, MC
通讯作者：
Brahimi-Horn, MC
影响因子：
5.8
作者：
Kruis, Tassilo;Klammt, Juergen;Pfaeffle, Roland
通讯作者：
Pfaeffle, Roland
DOI：
10.1152/ajplung.00050.2001
发表时间：
2002-03-01
影响因子：
4.9
作者：
Srinivasan, S;Strange, J;Bruce, MC
通讯作者：
Bruce, MC