The semaphorins are a large family of proteins that act as guidance signals for axons and dendrites. The class 4 semaphorins are integral membrane proteins that are widely expressed throughout the nervous system. Here, we show that a subclass of these semaphorins is characterized by a PDZ-binding motif at their carboxy-terminus. This sequence mediates the interaction with the post-synaptic density protein PSD-95/ SAP90. Co-expression of Sema4B with PSD-95 in COS 7 cells results in the clustering of Sema4B. Sema4B co-localizes with PSD-95 at synaptic contacts between cultured hippocampal neurons. This synaptic localization depends on the presence of the PDZ-binding motif.
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 -catenin, a central component of the canonical Wnt signaling pathway. Overexpression of RPTP suppressed the activity of a -catenin responsive promoter in the midbrain and reduced progenitor cell proliferation. Cotransfection of Wnt1 or of a stabilized form of -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 -catenin.
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