A role for receptor protein tyrosine phosphatase lambda in midbrain development.

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 lambda (RPTPlambda) is part of the complex molecular network that maintains and shapes the MHB region. RPTPlambda is expressed in a tight band of cells in the caudal midbrain, anterior to the transverse ring of Wnt1 expression. Forced expression of RPTPlambda across the mid-hindbrain region repressed expression of Wnt1, whereas RNA interference-mediated knock-down of RPTPlambda resulted in expansion and distortion of the Wnt1 domain. When ectopically expressed in the mesencephalon, RPTPlambda specifically inhibited the induction of Wnt1 expression after subsequent stimulation with Fgf8. Reduced Wnt1 expression after RPTPlambda transfection correlated with a decrease in Ras- mitogen-activated protein kinase activity at the MHB. We further show that in the embryonic midbrain, RPTPlambda can bind to beta-catenin, a central component of the canonical Wnt signaling pathway. Overexpression of RPTPlambda suppressed the activity of a beta-catenin responsive promoter in the midbrain and reduced progenitor cell proliferation. Cotransfection of Wnt1 or of a stabilized form of beta-catenin together with RPTPlambda partially rescued the RPTPlambda-mediated proliferation defect. Together, these data suggest that RPTPlambda 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 beta-catenin.