Novel receptor protein tyrosine phosphatase (RPTP?) and acidic fibroblast growth factor (FGF-1) transcripts delineate a rostrocaudal boundary in the granule cell layer of the murine cerebellar cortex

McAndrew, Patricia; Frostholm, Adrienne; Evans, James E.; Zdilar, Darko; Goldowitz, Dan; Chiu, Ing‐Ming; Burghes, Arthur H.M.; Rotter, Andrej

doi:10.1002/(sici)1096-9861(19980222)391:4<444::aid-cne3>3.0.co;2-0

Cited by 34 publications

(23 citation statements)

References 73 publications

(62 reference statements)

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“…2 c-f and i). Expression of Fgf-1, an anterior granule compartment marker (15), and Igfbpl1, an additional growth factor pathway component, were not altered (SI Fig. 21 c-f), indicating that the decrease in Igfbp5 was specific and not due to a general expression deficiency of all anterior compartment genes or growth factors.…”

Section: Resultsmentioning

confidence: 97%

The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7

Gatchel¹,

Watase

Thaller³

et al. 2008

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

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Polyglutamine diseases are inherited neurodegenerative disorders caused by expansion of CAG repeats encoding a glutamine tract in the disease-causing proteins. There are nine disorders, each having distinct features but also clinical and pathological similarities. In particular, spinocerebellar ataxia type 1 and 7 (SCA1 and SCA7) patients manifest cerebellar ataxia with degeneration of Purkinje cells. To determine whether the disorders share molecular pathogenic events, we studied two mouse models of SCA1 and SCA7 that express the glutamine-expanded protein from the respective endogenous loci. We found common transcriptional changes, with down-regulation of insulin-like growth factor binding protein 5 (Igfbp5) representing one of the most robust changes. Igfbp5 down-regulation occurred in granule neurons through a non-cellautonomous mechanism and was concomitant with activation of the insulin-like growth factor (IGF) pathway and the type I IGF receptor on Purkinje cells. These data define one common pathogenic response in SCA1 and SCA7 and reveal the importance of intercellular mechanisms in their pathogenesis.cerebellum ͉ neurodegeneration ͉ polyglutamine ͉ Purkinje cell ͉ granule neuron P olyglutamine diseases are a group of inherited neurodegenerative disorders that include spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, and 17 as well as Huntington disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), and spinal bulbar muscular atrophy (SBMA). They are caused by expansion of CAG repeats encoding a polyglutamine tract in different proteins (1). Evidence suggests that the polyglutamine expansion confers toxicity predominantly through a gain-of-function mechanism, although loss of function may also play a role (1, 2). Despite widespread expression of the disease proteins in the central nervous system (CNS), there is selective vulnerability of specific neurons in each disease (1). Such selective neuronal vulnerability gives rise to the specific features of each disease.SCA1 and SCA7 have distinct features while also sharing some key similarities. In SCA1, primary symptoms include ataxia, dysarthria, and bulbar dysfunction, whereas cognitive impairment is more varied (1). This presentation is associated with cerebellar atrophy and loss of Purkinje cells (PCs) and secondary loss of granule neurons (1). In SCA7, progressive visual loss, cerebellar ataxia, and dysarthria are the most common clinical features (3). In addition to retinal degeneration, cerebellar PCs and neurons of the dentate nucleus and inferior olive are among the earliest to degenerate (3).Given that SCA1 and SCA7 share a cerebellar degenerative phenotype, we proposed that some shared molecular changes might occur in both diseases, and that common molecular alterations could pinpoint pathways that could be targeted to modulate or monitor the pathogenesis of more than one disease. We focused on transcriptional changes because both ATXN1 and ATXN7 play roles in transcriptional regulation (4-8), and transcriptional defects can be detected in e...

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Section: Resultsmentioning

confidence: 97%

The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7

Gatchel¹,

Watase

Thaller³

et al. 2008

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

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“…RPTPρ is the most recently isolated member of the IIB family [6, 7]. Northern blot and in situ hybridization studies have shown that RPTPρ is largely restricted to the central nervous system [6].…”

Section: Introductionmentioning

confidence: 99%

“…Northern blot and in situ hybridization studies have shown that RPTPρ is largely restricted to the central nervous system [6]. Within the CNS, expression is developmentally regulated and, in the mouse, delineates a unique boundary region in the granule cell layer of the cerebellar cortex [7]. Motifs in the RPTPρ extracellular segment (MAM, Ig and FN-III domains) are commonly found in cell adhesion molecules.…”

Section: Introductionmentioning

confidence: 99%

Genomic organization and alternative splicing of the human and mouse RPTPρ genes

et al. 2001

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BackgroundReceptor protein tyrosine phosphatase rho (RPTPρ, gene symbol PTPRT) is a member of the type IIB RPTP family. These transmembrane molecules have been linked to signal transduction, cell adhesion and neurite extension. The extracellular segment contains MAM, Ig-like and fibronectin type III domains, and the intracellular segment contains two phosphatase domains. The human RPTPρ gene is located on chromosome 20q12-13.1, and the mouse gene is located on a syntenic region of chromosome 2. RPTPρ expression is restricted to the central nervous system.ResultsThe cloning of the mouse cDNA, identification of alternatively spliced exons, detection of an 8 kb 3'-UTR, and the genomic organization of human and mouse RPTPρ genes are described. The two genes are comprised of at least 33 exons. Both RPTPρ genes span over 1 Mbp and are the largest RPTP genes characterized. Exons encoding the extracellular segment through the intracellular juxtamembrane 'wedge' region are widely spaced, with introns ranging from 9.7 to 303.7 kb. In contrast, exons encoding the two phosphatase domains are more tightly clustered, with 15 exons spanning ∼ 60 kb, and introns ranging in size from 0.6 kb to 13.1 kb. Phase 0 introns predominate in the intracellular, and phase 1 in the extracellular segment.ConclusionsWe report the first genomic characterization of a RPTP type IIB gene. Alternatively spliced variants may result in different RPTPρ isoforms. Our findings suggest that RPTPρ extracellular and intracellular segments originated as separate modular proteins that fused into a single transmembrane molecule during a later evolutionary period.

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“…Previously, we have described the genomic structure of human PTPρ [8] and have shown that the transcript is expressed primarily in the central nervous system where it delineates a distinct developmental compartment in the cerebellar cortex [9,10]. In the present study, the genomic structures of all four murine R2B genes (PTPκ, PTPμ, PTPρ and PCP-2) were compared, and their expression localized to specific cell types within the central nervous system.…”

Section: Introductionmentioning

confidence: 91%

Genomic structure and alternative splicing of murine R2B receptor protein tyrosine phosphatases (PTPκ, μ, ρ and PCP-2)

et al. 2004

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Background: Four genes designated as PTPRK (PTPκ), PTPRL/U (PCP-2), PTPRM (PTPµ) and PTPRT (PTPρ) code for a subfamily (type R2B) of receptor protein tyrosine phosphatases (RPTPs) uniquely characterized by the presence of an N-terminal MAM domain. These transmembrane molecules have been implicated in homophilic cell adhesion. In the human, the PTPRK gene is located on chromosome 6, PTPRL/U on 1, PTPRM on 18 and PTPRT on 20. In the mouse, the four genes ptprk, ptprl, ptprm and ptprt are located in syntenic regions of chromosomes 10, 4, 17 and 2, respectively.

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Novel receptor protein tyrosine phosphatase (RPTP?) and acidic fibroblast growth factor (FGF-1) transcripts delineate a rostrocaudal boundary in the granule cell layer of the murine cerebellar cortex

Cited by 34 publications

References 73 publications

The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7

The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7

Genomic organization and alternative splicing of the human and mouse RPTPρ genes

Genomic structure and alternative splicing of murine R2B receptor protein tyrosine phosphatases (PTPκ, μ, ρ and PCP-2)

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