Insulin‐like growth factor II receptor, transforming growth factor‐β, and Cdk4 expression and the developmental epigenetics of mouse palate morphogenesis and dysmorphogenesis
Insulin‐like growth factor II receptor, transforming growth factor‐β, and Cdk4 expression and the developmental epigenetics of mouse palate morphogenesis and dysmorphogenesis
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胰岛素样生长因子 II 受体、转化生长因子-β 和 Cdk4 表达以及小鼠上腭形态发生和畸形发生的发育表观遗传学
作者：
M. Melnick;Haiming Chen;S. Buckley;D. Warburton;T. Jaskoll
B10/B10.A同源小鼠对用作鉴定与胚胎腭和其他器官的形态发生和畸形发生相关的特定基因的模型。本报告描述了我们对Fraser-Juriloff范式的初步研究，该范式提出畸形易感性是由正常发育模式中的遗传决定的差异引起的。具体而言，我们评估了Igf 2 r基因表达、转化生长因子-β（TGF-β）活化和cdk 4基因表达之间的关系。通过使用原位杂交、RNA酶保护试验、间接免疫荧光、蛋白质印迹和生物测定，我们显示：1）在发育的腭中存在胰岛素样生长因子II（IGF-II）、IGF-II受体（IGF-IIR）、IGF-IR、TGF-β、纤溶酶原、纤溶酶原激活物[尿激酶纤溶酶原激活物（uPA）和组织纤溶酶原激活物（tPA）]和Cdk 4; 2）在胚胎第14天（E14），这是腭生长的关键一天，B10.A胚胎的IGF-IIR mRNA比B10高82%; 3）在E14，B10.A胚胎腭的活性TGF-β2水平比B10高57%，尽管总TGF-β2几乎相同;和4）在E14，B10胚胎腭部具有比B10.A腭部高52%的Cdk 4 mRNA水平，这是细胞周期进展的量度。由于潜伏性TGF-β的细胞活化似乎需要与IGF-IIR的甘露糖-6-磷酸（M6 P）结合位点结合，并且是纤溶酶和纤溶酶原激活剂依赖性的，因此IGF-IIR水平与活性TGF-β2水平的正相关性似乎是关键。因此，G1期晚期TGF-β2/IGF-IIR介导的生长抑制的菌株差异似乎可以解释B10.A腭相对于B10的生长和发育较慢。E14 B10.A胚胎中皮质类固醇（CORT）暴露水平升高显著增加TGF-β水平，其中87%为TGF-β2，以及活性TGF-β水平，其中64%为TGF-β2。在没有外源性CORT的情况下，B10.A胚胎没有裂缝;因此，我们提出了发病机制的概述：生长较慢的B10.A胚胎具有IGF-IIR的上调，其用于将IGF-II与促进生长的IGF-IR隔离，并结合更多CORT上调的潜伏性TGF-β2，用于随后的纤溶酶依赖性激活;更高水平的TGF-β2信号转导下调Cdk 4，并在腭裂发生的关键阶段导致更大的腭裂生长抑制，从而导致腭裂。我们提出了一个与细胞增殖相关的信息处理的表观遗传模型。该模型是一个动态网络，使用连续逻辑从不断变化的条件中学习规则。Dev. Dyn. 1998;211：11-25.© 1998 Wiley利斯公司
The B10/B10.A congenic mouse pair serves as a model for identifying specific genes related to morphogenesis and dysmorphogenesis of the embryonic palate and other organs. The present report describes our initial investigation of the Fraser‐Juriloff paradigm, which proposes that susceptibility to malformation results from genetically determined differences in normal developmental patterns. Specifically, we evaluated the relationship between Igf2r gene expression, transforming growth factor‐β (TGF‐β) activation, and cdk4 gene expression. By using in situ hybridization, RNase protection assays, indirect immunofluorescence, Western blots, and bioassays, we show 1) the presence of insulin‐like growth factor II (IGF‐II), IGF‐II receptor (IGF‐IIR), IGF‐IR, TGF‐β, plasminogen, plasminogen activators [urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA)], and Cdk4 in developing palates; 2) on embryonic day 14 (E14), which is a critical day for palatal growth, B10.A embryos have 82% greater IGF‐IIR mRNA than B10; 3) on E14, B10.A embryonic palates have a 57% greater level of active TGF‐β2 than B10, although the total TGF‐β2 is nearly identical; and 4) on E14, B10 embryonic palates have a 52% greater level of Cdk4 mRNA than B10.A palates, a measure of cell cycle progression. Because cellular activation of latent TGF‐β appears to require binding to the mannose‐6‐phosphate (M6P) binding site of the IGF‐IIR and is plasmin and plasminogen activator dependent, the positive correlation of IGF‐IIR levels and active TGF‐β2 levels seems to be key. Thus, the strain variation of TGF‐β2/IGF‐IIR‐mediated growth inhibition in late G1 phase would appear to account for the slower growth and development of B10.A palates relative to B10. Elevated corticosteroid (CORT) exposure in E14 B10.A embryos significantly increases TGF‐β levels, 87% of which is TGF‐β2, as well as the levels of active TGF‐β, 64% of which is TGF‐β2. Without exogenous CORT, B10.A embryos do not have clefts; hence, we present an outline of pathogenesis: slower growing B10.A embryos have an up‐regulation of IGF‐IIR, which serves to sequester IGF‐II from the growth‐promoting IGF‐IR and to bind more CORT‐up‐regulated, latent TGF‐β2 for subsequent plasmin‐dependent activation; higher levels of TGF‐β2 signaling down‐regulate Cdk4 and result in greater palatal growth inhibition at a critical stage of palatogenesis and, thus, cleft palate. We present an epigenetic model of information processing related to cell proliferation. The model is a dynamical network that uses continuous logic to learn its rules from changing conditions. Dev. Dyn. 1998;211:11–25. © 1998 Wiley‐Liss, Inc.
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影响因子：
2.9
作者：
ABE, M;HARPEL, JG;RIFKIN, DB
通讯作者：
RIFKIN, DB
影响因子：
20.3
作者：
John I. Jones;D. Clemmons
通讯作者：
John I. Jones;D. Clemmons
具有类固醇敏感性差异的同系小鼠品系中的限制性片段长度多态性、糖皮质激素受体和苯妥英诱导的腭裂。
DOI：
--
发表时间：
1991
期刊：
Journal of craniofacial genetics and developmental biology
影响因子：
--
作者：
Gasser,DL;Goldner-Sauve,A;Katsumata,M;Goldman,AS
通讯作者：
Goldman,AS
糖皮质激素和苯妥英诱发腭裂的生化机制。
影响因子：
--
作者：
Goldman,AS
通讯作者：
Goldman,AS
小鼠主要组织相容性复合体 (H-2) 和胎儿肺发育：对人类肺成熟的影响。
DOI：
10.1002/ajmg.1320350124
发表时间：
1990
期刊：
American journal of medical genetics
影响因子：
--
作者：
Hu,CC;Jaskoll,TF;Minkin,C;Melnick,M
通讯作者：
Melnick,M