Dual Functions for LTBP in Lung Development: LTBP-4 Independently Modulates Elastogenesis and TGF-β Activity
Dual Functions for LTBP in Lung Development: LTBP-4 Independently Modulates Elastogenesis and TGF-β Activity
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DOI：
10.1002/jcp.21643
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发表时间：
2009-04-01
影响因子：
5.6
通讯作者：
Rifkin, Daniel B.
中科院分区：
文献类型：
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作者：
Dabovic, Branka;Chen, Yan;Rifkin, Daniel B.
潜在 TGF-β 结合蛋白 (LTBP) -1、-3 和 -4 是细胞外蛋白，有助于潜在 TGF-β 的分泌和定位。小鼠中 LTBP-4S 的无效突变会导致末梢气囊、弹性蛋白碎片和结肠癌的分化缺陷。我们研究了从胚胎第 14.5 天 (E 14.5) 到出生后第 7 天 (P7) 的肺发育，以确定弹性蛋白组织缺陷何时开始，并进一步检查 Ltbp4S-/- 肺中 TGF-β 信号水平与气囊分隔的关系。我们发现，早在 E 14.5 时，弹性生成缺陷就已可见，并且在肺泡壁、血管介质和下方气道上皮中得以维持。气囊分隔缺陷与过度的 TGF-β 信号传导有关，可通过降低 TGF-β 2 水平来逆转。因此，表型并不直接反映 TGF-β 1 的变化，TGF-β 1 是已知与 LTBP-4 复合的唯一 TGF-β 亚型。气囊分隔缺陷的逆转与弹性生成的正常化无关，表明 LTBP-4 作为肺中弹性纤维组装和 TGF-β 水平的调节剂具有两种不同的功能。
The latent TGF-beta binding proteins (LTBP) -1, -3, and -4 are extracellular proteins that assist in the secretion and localization of latent TGF-beta. The null mutation of LTBP-4S in mice causes defects in the differentiation of terminal air-sacs, fragmented elastin, and colon carcinomas. We investigated lung development from embryonic day 14.5 (E 14.5) to day 7 after birth (P7) in order to determine when the defects in elastin organization initiate and to further examine the relation of TGF-beta signaling levels and air-sac septation in Ltbp4S-/- lungs. We found that defects in elastogenesis are visible as early as E 14.5 and are maintained in the alveolar walls, in blood vessel media, and subjacent airway epithelium. The air-sac septation defect was associated with excessive TGF-beta signaling and was reversed by lowering TGF-beta 2 levels. Thus, the phenotype is not directly reflective of a change in TGF-beta 1, the only TGF-beta isoform known to complex with LTBP-4. Reversal of the air-sac septation defect was not associated with normalization of the elastogenesis indicating two separate functions of LTBP-4 as a regulator of elastic fiber assembly and TGF-beta levels in lungs.