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In Vivo Induction of Glial Cell Proliferation and Axonal Outgrowth and Myelination by Brain-Derived Neurotrophic Factor

Department of Molecular Animal Physiology (D.M.d.G., A.J.M.C., F.v.H., G.J.M.M.), Nijmegen Center for Molecular Life Sciences (NCMLS), Institute for Neuroscience, Faculty of Science, and Department of Pathology (A.V.), Radboud University Medical Centre, Nijmegen 6525 GA, The Netherlands

Address all correspondence and requests for reprints to: Dr. G. J. M. Martens, Department of Molecular Animal Physiology, Institute for Neuroscience, Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen, Geert Grooteplein Zuid 28, 6525 GA Nijmegen, The Netherlands. E-mail: g.martens{at}ncmls.ru.nl.

Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of neuronal cell survival and differentiation factors but is thought to be involved in neuronal cell proliferation and myelination as well. To explore the role of BDNF in vivo, we employed the intermediate pituitary melanotrope cells of the amphibian Xenopus laevis as a model system. These cells mediate background adaptation of the animal by producing high levels of the prohormone proopiomelanocortin (POMC) when the animal is black adapted. We used stable X. transgenesis in combination with the POMC gene promoter to generate transgenic frogs overexpressing BDNF specifically and physiologically inducible in the melanotrope cells. Intriguingly, an approximately 25-fold overexpression of BDNF resulted in hyperplastic glial cells and myelinated axons infiltrating the pituitary, whereby the transgenic melanotrope cells became located dispersed among the induced tissue. The infiltrating glial cells and axons originated from both peripheral and central nervous system sources. The formation of the phenotype started around tadpole stage 50 and was induced by placing white-adapted transgenics on a black background, i.e. after activation of transgene expression. The severity of the phenotype depended on the level of transgene expression, because the intermediate pituitaries from transgenic animals raised on a white background or from transgenics with only an approximately 5-fold BDNF overexpression were essentially not affected. In conclusion, we show in a physiological context that, besides its classical role as neuronal cell survival and differentiation factor, in vivo BDNF can also induce glial cell proliferation as well as axonal outgrowth and myelination.