The Journal of Neuroscience, June 11, 2008, 28(24):6152-6164; doi:10.1523/JNEUROSCI.5593-07.2008
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Development/Plasticity/Repair
A Role for Receptor Protein Tyrosine Phosphatase 
in Midbrain Development
Anja Badde and
Dorothea Schulte
Department of Neuroanatomy, Max Planck Institute for Brain Research, 60528 Frankfurt, Germany
Correspondence should be addressed to Dorothea Schulte, Department of Neuroanatomy, Max Planck Institute for Brain Research, Deutschordenstrasse 46, 60528 Frankfurt, Germany. Email: schulte{at}mpih-frankfurt.mpg.de
The mid-hindbrain boundary (MHB) harbors an important organizing center for the adjacent brain regions. Here, we present evidence that the receptor protein tyrosine phosphatase 
(RPTP) is part of the complex molecular network that maintains and shapes the MHB region. RPTP is expressed in a tight band of cells in the caudal midbrain, anterior to the transverse ring of Wnt1 expression. Forced expression of RPTP across the mid-hindbrain region repressed expression of Wnt1, whereas RNA interference-mediated knock-down of RPTP resulted in expansion and distortion of the Wnt1 domain. When ectopically expressed in the mesencephalon, RPTP specifically inhibited the induction of Wnt1 expression after subsequent stimulation with Fgf8. Reduced Wnt1 expression after RPTP transfection correlated with a decrease in Ras- mitogen-activated protein kinase activity at the MHB. We further show that in the embryonic midbrain, RPTP can bind to β-catenin, a central component of the canonical Wnt signaling pathway. Overexpression of RPTP suppressed the activity of a β-catenin responsive promoter in the midbrain and reduced progenitor cell proliferation. Cotransfection of Wnt1 or of a stabilized form of β-catenin together with RPTP partially rescued the RPTP-mediated proliferation defect. Together, these data suggest that RPTP may play a dual role in the control of midbrain development: as a negative modulator of Fgf8-induced Wnt1 expression at the MHB, which may help to confine the Wnt1 domain to it characteristic tight ring at the MHB; and as an inhibitor of canonical Wnt signaling through interaction with and presumably sequestration of β-catenin.
Key words: RPTP
; Fgf8; Wnt1; β-catenin; midbrain; chick
Received July 4, 2007;
revised March 21, 2008;
accepted April 17, 2008.
Correspondence should be addressed to Dorothea Schulte, Department of Neuroanatomy, Max Planck Institute for Brain Research, Deutschordenstrasse 46, 60528 Frankfurt, Germany. Email: schulte{at}mpih-frankfurt.mpg.de
