Editors' ChoiceDevelopment

Pruning the Brain

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Science's STKE  25 Jan 2005:
Vol. 2005, Issue 268, pp. tw34
DOI: 10.1126/stke.2682005tw34

Thrombopoietin (TPO) and erythropoietin (EPO) both act as hematopoietic growth factors: TPO stimulates platelet formation, whereas EPO stimulates erythrocyte formation. Noting that EPO acts as a survival factor in the developing and stressed adult brain, Ehrenreich et al. investigated the possible role of brain TPO. Whereas the amount of mouse brain EPO mRNA decreased between embryonic day 11 (E11) and E15, that of TPO continued to rise into adulthood. Similarly, brain EPO protein expression was decreased in the adult compared with that at E11 or E13, whereas TPO protein expression was greater in the adult. In primary cultures of hippocampal neurons, hypoxia stimulated an increase in EPO mRNA and protein, whereas it caused a decrease in TPO mRNA and protein. Under normoxic conditions, concentrations of TPO that stimulated hematopoietic stem cell proliferation unexpectedly promoted the death of cultured hippocampal neurons, an effect that was blocked by EPO as well as by granulocyte colony-stimulating factor, neurotrophin-3, or brain-derived neurotrophic factor (BDNF). Pharmacological inhibition of the protein kinase JAK2, extracellular signal-regulated kinase (ERK1/2), or caspase-3 blocked TPO-induced neuronal death, whereas inhibition of phosphatidylinositol 3-kinase (PI3K) blocked the ability of EPO to rescue neurons from TPO-mediated death. TPO enhanced apoptosis of young neurons (neurons that expressed β-tubulin III) in juvenile rats in a model of moderate hypoxic-ischemic brain injury. Thus, whereas other growth factors enhance neuronal survival, the authors propose that TPO may contribute to the pruning of extraneous neurons that takes place during late stages of brain development.

H. Ehrenreich, M. Hasselblatt, F. Knerlich, N. von Ahsen, S. Jacob, S. Sperling, H. Wolge, K. Vehmeyer, K.-A. Nave, A.-L. Sirén, A hematopoietic growth factor, thrombopoietin, has a proapoptotic role in the brain. Proc. Natl. Acad. Sci. U.S.A. 102, 862-867 (2005). [Abstract] [Full Text]

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