An essential role for Frizzled5 in neuronal survival in the parafascicular nucleus of the thalamus.
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.
Departments of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Chunqiao
C
Liu
Yanshu
Y
Wang
Philip M
PM
Smallwood
Jeremy
J
Nathans
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002490:Central Nervous System / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D004622:Embryo, Mammalian; D004965:Estrogen Antagonists / Q000494:pharmacology; D051157:Frizzled Receptors / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D020646:Intralaminar Thalamic Nuclei / Q000166:cytology*; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D014162:Transfection / Q000379:methods; D015430:Weight Gain / Q000235:genetics; D051153:Wnt Proteins / Q000502:physiology
D004965:Estrogen Antagonists; D051157:Frizzled Receptors; C403211:Fzd5 protein, mouse; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins; D013629:Tamoxifen; C016601:afimoxifene; D000469:Alkaline Phosphatase