An Essential Role for Frizzled5 in Neuronal Survival in the Parafascicular Nucleus of the Thalamus

Abstract

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 ␤-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 ␤-catenin, a mediator of canonical Wnt signaling, are both downregulated in the Fz5 Ϫ/Ϫ 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 WntFrizzled signaling could be the cause of neuronal loss in degenerative CNS diseases.

Blocking Receptor Protein Tyrosine Phosphatase β /ζ: A Potential Therapeutic Strategy for Parkinsons Disease

“…Thus, increases of -catenin function in ventral mesencephalic precursors result in increased dopamine neuron differentiation [61]. These results fit perfectly with recent data demonstrating that downregulation of -catenin levels could be part of the mechanisms involved in the neuronal loss characteristic of neurodegenerative diseases such as Parkinson´s disease [62].…”

The effects of nigrostriatal dopamine depletion on the thalamic parafascicular nucleus

“…Recent studies have found that PF neurons, in addition to using glutamate as a transmitter, express certain other proteins, including cerebellin1 (Cbln1; Kusnoor et al, 2010), the leucine-rich repeat-containing G protein coupled receptor 8 (LGR8; Sedaghat et al, 2008), and frizzled5 (Fz5), a wnt receptor (Liu et al, 2008). Interestingly, conditional knockouts of Fz5 lead to loss of PF neurons (Liu et al, 2008), suggesting at least one mechanism independent of dopamine signaling that may contribute to degeneration of PF neurons in PD.…”

“…Interestingly, conditional knockouts of Fz5 lead to loss of PF neurons (Liu et al, 2008), suggesting at least one mechanism independent of dopamine signaling that may contribute to degeneration of PF neurons in PD.…”

Frizzled Receptors in Development and Disease

“…In the brain, Fz5 is expressed selectively in neurons in the parafascicular nucleus (PFN) of the thalamus, and Fz5 CKO/CKO ;Sox2-Cre mice show a progressive loss of PFN neurons over the first several months of postnatal life (Liu, Wang, Smallwood, & Nathans, 2008). Genetic mosaic experiments in which Fz5 −/− cells are marked by expression of a reporter show that this loss is cell autonomous.…”

“…Numerous changes in gene expression in PFN neurons precede neuronal loss, including downregulation of the genes coding for beta-catenin, Wnt4, and Wnt9b, suggesting that a Fz5-dependent positive feedback loop maintains canonical Wnt signaling in the PFN. The physiological role of the PFN is not well understood, but the work of Liu et al (2008) implicates the PFN in sensorimotor function because loss of PFN neurons in Fz5 CKO/CKO ;Sox2-Cre mice is accompanied by impaired motor coordination.…”