Localization of a retroviral element within the rd gene coding for the beta subunit of cGMP phosphodiesterase.

Bowes, Cathy; Li, Tiansen; Frankel, Wayne N.; Danciger, Michael; Coffin, John M.; Applebury, Meredithe L.; Farber, Débora B.

doi:10.1073/pnas.90.7.2955

Cited by 191 publications

(92 citation statements)

References 24 publications

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“…To make certain that the rd mutations were absent from our strains, we sequenced the entire PDE-␤ gene from our Aipl1 Ϫ/Ϫ mice. Neither of the two PDE-␤ mutations linked to rd, Y347Stop or the proviral insertion in intron 1 (25)(26)(27), was present in the Aipl1 Ϫ/Ϫ mice that we characterized (see Fig. 8, which is published as supporting information on the PNAS web site).…”

Section: Disorganization Of Photoreceptor Outer Segmentsmentioning

confidence: 99%

Leber congenital amaurosis linked to AIPL1: A mouse model reveals destabilization of cGMP phosphodiesterase

Ramamurthy

Niemi

Reh

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

164

221

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Leber congenital amaurosis (LCA4) has been linked to mutations in the photoreceptor-specific gene Aryl hydrocarbon interacting protein like 1 (Aipl1). To investigate the essential role of AIPL1 in retina, we generated a mouse model of LCA by inactivating the Aipl1 gene. In Aipl1 ؊/؊ retinas, the outer nuclear layer develops normally, but rods and cones then quickly degenerate. Aipl1 ؊/؊ mice have highly disorganized, short, fragmented photoreceptor outer segments and lack both rod and cone electroretinogram responses. Recent biochemical evidence indicates that AIPL1 can enhance protein farnesylation. Our study reveals that rod cGMP phosphodiesterase, a farnesylated protein, is absent and cGMP levels are elevated in AIPL1 ؊/؊ retinas before the onset of degeneration. Our findings demonstrate that AIPL1 enhances the stability of phosphodiesterase and is essential for photoreceptor viability. L eber congenital amaurosis (LCA) has the earliest onset and is the most severe form of inherited retinopathy in humans. LCA is genetically heterogeneous and is generally inherited in an autosomal recessive fashion. LCA is characterized by complete blindness and the near absence of electrical responses to light within 1 year of birth. LCA has been linked to mutations in the gene encoding Aipl1 (1-3). The vast majority of these mutations in Aipl1 are linked to LCA, but a few C-terminal mutations are linked to two other retinal diseases, cone-rod dystrophy and juvenile retinitis pigmentosa (3).AIPL1 is expressed only in retina and pineal gland (1). In adult mouse retina, it is found within the outer plexiform layer and the inner segments of photoreceptors; in humans, AIPL1 is expressed in both developing rods and cones and mature rods (4, 5). Two possibilities for the essential role for AIPL1 in retina have been proposed (4). The first is that AIPL1 enhances an essential farnesylation reaction. Farnesylation is a specific type of prenylation, the addition of a farnesyl or geranylgeranyl residue to specific proteins. Several retinal proteins, cGMP phosphodiesterase (PDE), transducin, and rhodopsin (Rho) kinase (RK) are known to be farnesylated (6-9). Prenylation of retinal proteins is required for maintenance of retinal cytoarchitecture and photoreceptor structure. Inhibition of prenylation causes degeneration of photoreceptor outer segments (10). Prenylation also greatly enhances the stability of cGMP PDE, a protein essential for photoreceptor survival (11). Prenylation of PDE is also necessary for its membrane association (11). These studies suggest that AIPL1 is necessary for the maintenance of photoreceptors. The second possible essential role for AIPL1 is the control of photoreceptor proliferation and or differentiation. AIPL1 interacts with Nedd8-ultimate buster 1 (NUB1), a ubiquitously expressed protein thought to play an important role in regulating cell cycle progression (12). Based on the NUB1 interaction, early expression of AIPL1 in human retina, and the severity of AIPL1 mutations linked to LCA, it has been proposed ...

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Section: Disorganization Of Photoreceptor Outer Segmentsmentioning

confidence: 99%

Leber congenital amaurosis linked to AIPL1: A mouse model reveals destabilization of cGMP phosphodiesterase

Ramamurthy

Niemi

Reh

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

164

221

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“…C3H/HeSnJ mice carry a recessive mutation that leads to retinal degeneration (Rd); therefore, all of the animals were genotyped using standard PCR to detect the Rd mutation (Bowes et al, 1993). Experiments were conducted using wt/wt or Rd1/wt animals.…”

Section: Experimental Animalsmentioning

confidence: 99%

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

García-Cerro

Rueda

Vidal

et al. 2017

Neurobiology of Disease

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The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including DYRK1A (dualspecificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology. Studies performed in vitro and in vivo in animal models overexpressing this gene have demonstrated that the DYRK1A gene also plays a crucial role in several neurodegenerative processes found in DS. The Ts65Dn (TS) mouse bears a partial triplication of several Hsa21 orthologous genes, including Dyrk1A, and replicates many DS-like abnormalities, including age-dependent cognitive decline, cholinergic neuron degeneration, increased levels of APP and Aβ, and tau hyperphosphorylation. To use a more direct approach to evaluate the role of the gene dosage of Dyrk1A on the neurodegenerative profile of this model, TS mice were crossed with Dyrk1A KO mice to obtain mice with a triplication of a segment of Mmu16 that includes this gene, mice that are trisomic for the same genes but only carry two copies of Dyrk1A, euploid mice with a normal Dyrk1A dosage, and CO animals with a single copy of Dyrk1A. Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aβ load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. Thus, the present study provides further support for the role of the Dyrk1A gene in several AD-like phenotypes found in TS mice and indicates that this gene could be a therapeutic target to treat AD in DS.

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“…codes for retinal degeneration in FVB mice (32)] had been selectively replaced by crossing with strains carrying the nondefective allele (V. Errijgers and R. F. Kooy, unpublished work). However, some earlier synaptoneurosome activation experiments used a ''blind'' variant of this strain that still possessed the Pde6b mutation.…”

mentioning

confidence: 99%

Fragile X mental retardation protein is necessary for neurotransmitter-activated protein translation at synapses

Weiler

Spangler

Klintsova

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

192

177

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Fragile X mental retardation is caused by absence of the RNAbinding protein fragile X mental retardation protein (FMRP), encoded by the FMR1 gene. There is increasing evidence that FMRP regulates transport and modulates translation of some mRNAs. We studied neurotransmitter-activated synaptic protein synthesis in fmr1-knockout mice. Synaptoneurosomes from knockout mice did not manifest accelerated polyribosome assembly or protein synthesis as it occurs in wild-type mice upon stimulation of group I metabotropic glutamate receptors. Direct activation of protein kinase C did not compensate in the knockout mouse, indicating that the FMRP-dependent step is further along the signaling pathway. Visual cortices of young knockout mice exhibited a lower proportion of dendritic spine synapses containing polyribosomes than did the cortices of wild-type mice, corroborating this finding in vivo. This deficit in rapid neurotransmitter-controlled local translation of specific proteins may contribute to morphological and functional abnormalities observed in patients with fragile X syndrome.dendrites ͉ metabotropic glutamate receptor ͉ mRNA ͉ plasticity ͉ ultrastructure F ragile X mental retardation syndrome is an inherited, Xlinked disorder. In most patients, methylation of an extreme expansion (200-1,000 repeats) of a (CGG)n trinucleotide repeat in the 5Ј UTR of the FMR1 gene blocks transcription of fmr1 mRNA (1). The resulting absence of fragile X mental retardation protein (FMRP) causes the syndrome, which is characterized by mental retardation, macroorchidism, and behavioral abnormalities (2). The brains of these patients exhibit an unusual, spindly appearance of the dendritic spines as well as an overabundance of spines (3, 4), a morphology that resembles early postnatal tissue.The function of FMRP is unknown; in neurons much of the protein is found in dendrites (5). FMRP contains RNA-binding elements (6) and is associated with actively translating polyribosomes in the brain (7-9). Several laboratories have described sets of mRNAs bound by FMRP (10-12), and specific motifs involved in FMRP binding of some mRNAs have been identified (13,14). Recently, we demonstrated (10) that several members of a subset of mRNAs bound by FMRP in intact cells are differentially distributed and͞or translated in dendritic, as compared to somatic, subcellular domains. This finding suggests direct involvement of FMRP in transport and͞or translation of mRNA in dendrites. Antar et al. (15) have demonstrated rapid transport of FMRP into dendrites upon KCl depolarization. We report here that a dynamic aspect of translation, neurotransmitter-induced rapid initiation, is directly impacted by the absence of FMRP.Protein translation in dendrites was suggested by early descriptions of postsynaptic polyribosomal aggregates (PRAs) during synaptogenesis and in the visual cortex of rats reared in complex environments, indicating the importance of local translation for synaptic plasticity (16,17). Components necessary for translation are present postsynaptic...

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Localization of a retroviral element within the rd gene coding for the beta subunit of cGMP phosphodiesterase.

Cited by 191 publications

References 24 publications

Leber congenital amaurosis linked to AIPL1: A mouse model reveals destabilization of cGMP phosphodiesterase

Leber congenital amaurosis linked to AIPL1: A mouse model reveals destabilization of cGMP phosphodiesterase

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

Fragile X mental retardation protein is necessary for neurotransmitter-activated protein translation at synapses

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