PDGF-A/PDGF alpha-receptor signaling is required for lung growth and the formation of alveoli but not for early lung branching morphogenesis
PDGF-A/PDGF alpha-receptor signaling is required for lung growth and the formation of alveoli but not for early lung branching morphogenesis
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DOI：
10.1002/dvdy.1225
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发表时间：
2002-01-01
影响因子：
2.5
通讯作者：
Betsholtz, C
中科院分区：
文献类型：
--
作者：
Boström, H;Gritli-Linde, A;Betsholtz, C
血小板源性生长因子 (PDGF) 构成由四种基因产物 (PDGF-A-D) 组成的家族，通过两种受体酪氨酸激酶（PDGFR α 和 β）发挥作用。三种配体（PDGF-A、-B 和 -C）以高亲和力与 PDGFR α 结合。小鼠中 pdgf-alpha 的敲除证明了 PDGF-A 在将平滑肌细胞募集到肺泡囊以及将其进一步划分为肺泡中的作用。尽管这是肺发育中较晚的出生后步骤，但先前已证明PDGF-α反义寡核苷酸可抑制体外大鼠肺外植体中的上皮分支，这反映了早期胚胎过程。这些相互矛盾的结果可能是由于母体将 PDGF-A 转移到敲除胚胎中替代了 pdgf-α 的遗传损失，或者体内存在其他 PDGFR α 激动剂（PDGF-B 和 -C），可能掩盖了 PDGF-A 对分支形态发生的影响。或者，pdgf-α反义寡核苷酸的施用影响了预期以外的其他过程。为了区分这些相反的可能性，我们分析了 pdgfr α -/- 胚胎和体外生长的肺原基的肺发育。我们的分析表明，虽然 pdgfr α -/- 肺和外植肺雏形比正常情况要小，但分支形态发生在质量上显得完整，并且至少持续到胚胎第 15.5 天，产生预期的传导气道和呼吸气道。我们的结论是，尽管 PDGFR α 上的 PDGF-AA 信号传导可能在整体肺生长中具有直接或间接作用，但它并不专门控制肺上皮的早期分支。 (C) 2002 Wiley-Liss, Inc.
Platelet-derived growth factors (PDGF) constitute a family of four gene products (PDGF-A-D) acting by means of two receptor tyrosine kinases, PDGFR alpha and beta. Three of the ligands (PDGF-A, -B, and -C) bind to PDGFR alpha with high affinity. Knockout of pdgf-alpha in mice has demonstrated a role for PDGF-A in the recruitment of smooth muscle cells to the alveolar sacs and their further compartmentalization into alveoli. Although this is a late, postnatal step in lung development, pdgf-alpha antisense oligonucleotides were previously shown to inhibit epithelial branching in rat lung explants in vitro, which reflects an early embryonic process. These conflicting results may be explained by substitution of genetic loss of pdgf-alpha by maternal transfer of PDGF-A to the knockout embryo or the presence of other PDGFR alpha agonists (PDGF-B and -C) in vivo, potentially masking an effect of PDGF-A on branching morphogenesis. Alternatively, the administration of pdgf-alpha antisense oligonucleotides affected other processes than the intended. To discriminate between these opposing possibilities, we have analyzed lung development in pdgfr alpha -/- embryos and lung primordia grown in vitro. Our analysis shows that, while the pdgfr alpha -/- lungs and explanted lung rudiments were smaller than normal, branching morphogenesis appears qualitatively intact and proceeds until at least embryonic day 15.5, generating both prospective conducting and respiratory airways. We conclude that, although PDGF-AA signaling over PDGFR alpha may have direct or indirect roles in overall lung growth, it does not specifically control early branching of the lung epithelium. (C) 2002 Wiley-Liss, Inc.