Reynolds Paul R, Mucenski Michael L, Whitsett Jeffrey A
Cincinnati Children's Hospital Medical Center, Division of Pulmonary Biology, Cincinnati, Ohio 45229-3039, USA.
Dev Dyn. 2003 Jun;227(2):227-37. doi: 10.1002/dvdy.10304.
Midkine (MK) is a 13-kDa heparin-binding growth factor that is thought to mediate developmental processes, including vasculogenesis, cell migration, and proliferation in various organs. To determine whether MK plays a role during lung morphogenesis, immunostaining for MK was assessed in mouse lung from embryonic day (E) 13 to postnatal day (PN) 24. MK was detected in mesenchymal and respiratory epithelial cells of the peripheral mouse lung from E13.0 to E15.5. From E18.5 to PN1, MK was observed primarily in epithelial cells lining conducting airways and peripheral lung saccules. By PN10, expression was no longer observed in respiratory epithelial cells but was readily detected in small blood vessels in the alveolar region of the lung. Although most respiratory epithelial cells uniformly expressed MK before E13.0, MK was restricted to subsets of cells by E18.5, colocalizing with the Clara cell secretory protein (CCSP) marker in conducting airways and with pro-SPC, a marker specific for alveolar type II pneumocytes. By PN10, MK was not detected in respiratory epithelial cells of the conducting airways and was closely associated with capillary networks. The sites of intense MK staining in the respiratory epithelial cells correlated with sites of expression of thyroid transcription factor (TTF) -1, a transcription factor regulating formation and gene expression in the lung parenchyma. TTF-1 enhanced transcription of the mouse MK gene promoter, acting on TTF-1 regulatory elements located in the 5'-region of the gene. Furthermore, MK expression was not detected in lungs of TTF-1 null mice. TTF-1 regulates expression of MK in the lung. The temporal/spatial distribution of midkine is consistent with a potential role in paracrine signaling during lung morphogenesis.
中期因子（MK）是一种13千道尔顿的肝素结合生长因子，被认为介导包括血管生成、细胞迁移以及各器官增殖在内的发育过程。为了确定MK在肺形态发生过程中是否发挥作用，我们对胚胎期第（E）13天到出生后第（PN）24天的小鼠肺组织进行了MK免疫染色评估。在胚胎期第13.0天到15.5天的小鼠外周肺组织的间充质和呼吸上皮细胞中检测到了MK。从胚胎期第18.5天到出生后第1天，MK主要在传导气道和外周肺囊泡的上皮细胞中观察到。到出生后第10天，在呼吸上皮细胞中不再观察到表达，但在肺肺泡区域的小血管中很容易检测到。尽管在胚胎期第13.0天之前大多数呼吸上皮细胞均一表达MK，但到胚胎期第18.5天，MK局限于细胞亚群，在传导气道中与克拉拉细胞分泌蛋白（CCSP）标记物共定位，在肺泡II型上皮细胞中与前表面活性蛋白C（pro-SPC）共定位，pro-SPC是肺泡II型上皮细胞的特异性标记物。到出生后第10天，在传导气道的呼吸上皮细胞中未检测到MK，且MK与毛细血管网络密切相关。呼吸上皮细胞中MK强染色的部位与甲状腺转录因子（TTF）-1的表达部位相关，TTF-1是一种调节肺实质形成和基因表达的转录因子。TTF-1增强小鼠MK基因启动子的转录，作用于位于该基因5'区域的TTF-1调控元件。此外，在TTF-1基因敲除小鼠的肺组织中未检测到MK表达。TTF-1调节肺中MK的表达。中期因子的时空分布与肺形态发生过程中旁分泌信号传导的潜在作用一致。
