afimoxifene and Weight-Gain

Frizzled5 (Fz5), a putative Wnt receptor, is expressed in the retina, hypothalamus, and the parafascicular nucleus (PFN) of the thalamus. By constructing Fz5 alleles in which beta-galactosidase replaces Fz5 or in which Cre-mediated recombination replaces Fz5 with alkaline phosphatase, we observe that Fz5 is required continuously and in a cell autonomous manner for the survival of adult PFN neurons, but is not required for proliferation, migration, or axonal growth and targeting of developing PFN neurons. A motor phenotype associated with loss of Fz5 establishes a role for the PFN in sensorimotor coordination. Transcripts coding for Wnt9b, the likely Fz5 ligand in vivo, and beta-catenin, a mediator of canonical Wnt signaling, are both downregulated in the Fz5(-/-) PFN, implying a positive feedback mechanism in which Wnt signaling is required to maintain the expression of Wnt signaling components. These data suggest that defects in Wnt-Frizzled signaling could be the cause of neuronal loss in degenerative CNS diseases.

Topics: Alkaline Phosphatase; Animals; Animals, Newborn; Behavior, Animal; Cell Survival; Cells, Cultured; Central Nervous System; Embryo, Mammalian; Estrogen Antagonists; Frizzled Receptors; Gene Expression Regulation, Developmental; Intralaminar Thalamic Nuclei; Mice; Mice, Transgenic; Microarray Analysis; Motor Activity; Mutation; Neurons; Receptors, G-Protein-Coupled; Signal Transduction; Tamoxifen; Transfection; Weight Gain; Wnt Proteins