Roles of midkine, a heparin-binding growth factor, in the fetal adrenal gland

妊娠中期人胎儿肾上腺（HFA）主要由两个区带组成，即确定区（DZ）和胎儿区（FZ）。虽然FZ分泌硫酸脱氢表雄酮，但DZ的功能尚不清楚。我们提出DZ表型是祖细胞的储库，这些祖细胞小且紧密堆积，其中许多是有丝分裂活性的。在这个项目中，我们研究了中期因子（MK）的表达，定位，功能和调节，肝素结合生长因子具有多种功能，在HFA。中期HFA的MK mRNA水平比成人肾上腺高4倍。MK免疫反应被发现丰富的整个HFA的细胞表面。令人感兴趣的是，MK在体外诱导DZ细胞的选择性增殖，从而深入了解DZ和FZ之间有丝分裂活性在体内差异的机制。药物干预表明PI 3-激酶、MEK和src家族激酶可能参与MK诱导的DZ细胞增殖。我们还发现，MK下调HSD 3B 2 mRNA在分离的DZ和FZ细胞，表明MK可能是一个组成部分的机制，在体内抑制HSD 3B 2的表达，独特的肾上腺表型在胎儿期观察。在MK信号传导中涉及的受体中，syndecan-3，硫酸乙酰肝素蛋白聚糖，仅位于DZ中。因此，多配体蛋白聚糖-3可能是介导MK的DZ选择性促有丝分裂作用的受体的候选者。最后，我们证明，促肾上腺皮质激素，主要调节或HFA的发展和功能，上调MK mRNA在分离的FZ细胞，这表明MK属于一个队列的生长因子调节促肾上腺皮质激素。总的来说，这些结果表明MK在HFA发育和功能中的关键作用。

The midgestation human fetal adrenal (HFA) is comprised primarily of two zones, the definitive zone (DZ) and the fetal zone (FZ). While the FZ secretes dehydroepiandrosterone sulfate, the function of the DZ is less clear. We have proposed that the DZ phenotype is that of a reservoir of progenitor cells which are small and tightly packed, many of which are mitotically active. In this project, we investigated expression, localization, function, and regulation of midkine (MK), a heparin-binding growth factor with multiple functions, in the HFA. MK mRNA levels in midgestaion HFA's were 4-fold higher than those in adult adrenals. MK immunoreactivity was found abundantly on cell surfaces throughout the HFA. Of interest, MK induced selective proliferation of DZ cells in vitro, providing insights into the mechanism underlying the distinct in vivo differences in mitotic activity between the DZ and FZ. Pharmacological interventions showed that PI 3-kinase, MEK, and src family kinases may be involved in MK-induced proliferation of DZ cells. We also showed that MK down-regulates HSD3B2 mRNA in isolated DZ and FZ cells, indicating that MK may be a component of the mechanisms that underlie in vivo suppression of HSD3B2 expression, the unique adrenal phenotype observed during fetal life. Among the receptors implicated in MK signaling, syndecan-3, a heparan sulfate proteoglycan, was localized only in the DZ. Thus, syndecan-3 could be a candidate for receptor(s) that mediate DZ-selective mitogenic effects of MK. Finally, we demonstrated that ACTH, the primary regulator or HFA development and function, up-regulates MK mRNA in isolated FZ cells, suggesting that MK belongs to a cohort of growth factors regulated by ACTH. Collectively, these results point to key roles of MK in HFA development and function.