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

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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.