Midkine (MK) and the highly related cytokine pleiotrophin (PTN) constitute the PTN/MK developmental gene family. The Mk and Ptn genes are essential for normal development of the catecholamine and renin-angiotensin pathways and the synthesis of different collagens. It is not known whether the Ptn and Mk genes regulate each other or whether PTN and MK are functionally redundant in development. We have now compared the levels If expression of Ptn and Mk in genetically deficient Mk- -/- and Ptn -/- mice and found highly significant increases in Pm gene expression in spinal cord, dorsal root ganglia, eye, heart, aorta, bladder, and urethra, but not in brain, bone marrow, testis, and lung of Mk -/- mice compared with wild type mice; a remarkable similar to 230-fold increase in Pm expression levels was found in heart of Mk -/- mice and highly significant but lesser increases were found in six other organs. Differences in levels of Mk-gene expression in Ptn -/- mice could not be detected in any of the organs tested. The data demonstrate that MK regulates Ptn gene expression with a high degree of organ specificity, suggesting that PM gene expression follows Mk gene expression in development, that the increase in Ptn gene expression is compensatory for the absence of MK in Mk- -/- mice, that PTN and MK share a high degree of functional redundancy, and that MK may be very important in the development of heart in mouse. (c) 2005 Elsevier Inc. All rights reserved.