A hematopoietic growth factor, thrombopoietin, has a proapoptotic role in the brain

Hannelore Ehrenreich ^*, , Martin Hasselblatt ^*, Friederike Knerlich ^*, Nico von Ahsen , Sonja Jacob ^*, Swetlana Sperling ^*, Helge Woldt ^*, Katalin Vehmeyer , Klaus-Armin Nave ^*, and Anna-Leena Sirén ^*

^*Max Planck Institute of Experimental Medicine and Departments of Clinical Chemistry and Hematology and Oncology, Georg-August University, 37075 Goettingen, Germany

Received for publication August 15, 2004.

Abstract: Central nervous and hematopoietic systems share developmental features. We report that thrombopoietin (TPO), a stimulator of platelet formation, acts in the brain as a counterpart of erythropoietin (EPO), a hematopoietic growth factor with neuroprotective properties. TPO is most prominent in postnatal brain, whereas EPO is abundant in embryonic brain and decreases postnatally. Upon hypoxia, EPO and its receptor are rapidly reexpressed, whereas neuronal TPO and its receptor are down-regulated. Unexpectedly, TPO is strongly proapoptotic in the brain, causing death of newly generated neurons through the Ras-extracellular signal-regulated kinase 1/2 pathway. This effect is not only inhibited by EPO but also by neurotrophins. We suggest that the proapoptotic function of TPO helps to select for neurons that have acquired target-derived neurotrophic support.

Key Words: astrocytes • erythropoietin • neurons • differentiation • development

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: En, embryonic day n; EPO, erythropoietin; EPOR, EPO receptor; ERK, extracellular signal-regulated kinase; ISOL, in situ oligo ligation; PI3K, phosphatidylinositol 3-kinase; Pn, postnatal day n; TPO, thrombopoietin; TPOR, TPO receptor.

To whom correspondence should be addressed. E-mail: ehrenreich{at}em.mpg.de.

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