Mice devoid of the glial fibrillary acidic protein develop normally and are susceptible to scrapie prions

Gomi, Hiroshi; Yokoyama, Takashi; Fujimoto, Kazushi; Ikeda, Toshio; Katoh, Akira; Itoh, Takeshi; Itohara, Shigeyoshi

doi:10.1016/0896-6273(95)90238-4

Cited by 243 publications

(164 citation statements)

References 57 publications

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“…The mouse embryonic stem (ES) cell line used was E14 (a gift of M. Hooper). Cell culture, targeting experiment, and microinjection of ES clones into C57BL/6J blastocysts were carried out as described previously (12). The mutation heterozygous mice were obtained by crossing the chimeras to C57BL/6J mice.…”

Section: Methodsmentioning

confidence: 99%

Unaltered Secretion of β-Amyloid Precursor Protein in Gelatinase A (Matrix Metalloproteinase 2)-deficient Mice

Itoh¹,

Ikeda²,

Gomi³

et al. 1997

Journal of Biological Chemistry

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328

225

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The ␤-amyloid peptide, which forms extracellular cerebral deposits in Alzheimer's disease, is derived from a large membrane-spanning glycoprotein referred to as the ␤-amyloid precursor protein (APP). The APP is normally cleaved within the ␤-amyloid region by a putative proteinase (␣-secretase) to generate large soluble amino-terminal derivatives of APP, and this event prevents the ␤-amyloid peptide formation. It has been suggested that the gelatinase A (matrix metalloproteinase 2, a 72-kDa type IV collagenase) may act either as ␣-secretase or as ␤-secretase. Mice devoid of gelatinase A generated by gene targeting develop normally, except for a subtle delay in their growth, thus providing a useful system to examine the role of gelatinase A in the cleavage and secretion of APP in vivo. We show here that APP is cleaved within the ␤-amyloid region and secreted into the extracellular milieu of brain and cultured fibroblasts without gelatinase A activity. The data suggest that gelatinase A does not play an essential role in the generation and release of soluble derivatives of APP at physiological conditions. Amyloid precursor protein (APP) 1 is an integral membrane protein that is produced by most cells (1). Several isoforms ranging from 365 to 770 amino acids are generated by alternative splicing of transcripts from the APP gene on the long arm of chromosome 21 (2). Proteolytic cleavage of APP by enzymes termed ␣-, ␤-, and ␥-secretases generates various APP fragments that are released from APP expressing cells (3). ␤-Amyloid peptides (A␤) of 40 -43 amino acids are released by the action of ␤-and ␥-secretases cleaving at or near residues 671 and 713 (numbers refer to APP 770 ), respectively (3). Cleavage of APP at a membrane proximal site by an ␣-secretase releases larger APP fragments (sAPP) and prevents generation of A␤. The absolute and relative amounts of various APP fragments that are released in the brain are thought to be of importance in the formation of first amorphous (diffuse) and then filamentous (amyloid) plaques that are characteristic of Alzheimer's disease. Two larger forms sAPP also known as protease nexin II have a Kunitz type serine protease inhibitor domain (4, 5). In addition all forms of sAPP have in the carboxyl-terminal region a domain that inhibits gelatinase A (matrix metalloproteinase 2, a 72-kDa type IV collagenase) activity (6). On the other hand, gelatinase A has been suggested to act on APP either as ␣-secretase (6) or as ␤-secretase (7), although the hypothesis is controversial (8, 9). To clarify the putative role of this enzyme, we studied APP fragmentation and release in gelatinase A knockout mice. MATERIALS AND METHODSGeneration of Gelatinase A Gene-deficient Mice-A genomic DNA clone of mouse gelatinase A (Clg4a) was isolated from a 129/Sv genomic library. The fragments used for constructing the targeting vector were a 2.0-kb HindIII fragment of the distal region of the promoter and a 4.5-kb XbaI-SacI fragment. In the resulting targeting construct, 5.9 kb containing the exon 1 were r...

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Section: Methodsmentioning

confidence: 99%

Unaltered Secretion of β-Amyloid Precursor Protein in Gelatinase A (Matrix Metalloproteinase 2)-deficient Mice

Itoh¹,

Ikeda²,

Gomi³

et al. 1997

Journal of Biological Chemistry

Self Cite

328

225

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“…In the adult CNS, astrocytes provide structural support to neighbouring cells as well as in¯uence the physiological properties of neighbouring neurons by secreting growth factors and regulating neurotransmitter levels (Gilman and Schrier, 1972;Janzer and Ra , 1987). Studies using GFAP-null mice indicate no gross developmental abnormalities, suggesting that small amounts of other proteins such as vimentin may compensate for lack of GFAP (Gomi et al, 1995). However, recent studies suggest that GFAP is important for astrocytic-neuronal interactions because GFAP-null mice have alterations in long-term potentiation (or long-lasting enhancement of synaptic e cacy) in the hippocampus (McCall et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Correlation of B-FABP and GFAP expression in malignant glioma

et al. 1998

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The murine brain fatty acid binding protein (B-FABP) is encoded by a developmentally regulated gene that is expressed in radial glial cells and immature astrocytes. We have cloned the human B-FABP gene and have mapped it to chromosome 6q22-23. We show that B-FABP mRNA is expressed in human malignant glioma tumor biopsies and in a subset of malignant glioma cell lines, as well as in human fetal retina and brain. Malignant glioma tumors are characterized by cytoplasmic bundles of glial ®brillary acidic protein (GFAP), a protein normally expressed in mature astrocytes. Establishment of malignant glioma cell lines often results in loss of GFAP. The subset of malignant glioma cell lines that express GFAP mRNA also express B-FABP mRNA. Co-localization experiments in cell lines indicate that the same cells produce both GFAP and B-FABP. We suggest that some malignant gliomas may be derived from astrocytic precursor cells which can express proteins that are normally produced at di erent developmental stages in the astrocytic di erentiation pathway.

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“…The deletion of GFAP expression by targeted gene knock-out does not appear overtly to disturb brain development or to perturb either neurogenesis or gliogenesis (Gomi et al, 1995;Pekny et al, 1995), which suggests that the roles played by GFAP in NSCs are not unique and that there is a capacity for redundancy of function among different intermediate filament proteins. Nevertheless, although GFAP expression may not be essential for NSC function, the expression of GFAP by postnatal and adult NSCs in vivo and in vitro provides an additional means of investigating their cellular identity, developmental origins, and cell biology by transgenic and other techniques.…”

Section: Gfap Expression By Adult Nscsmentioning

confidence: 99%

The Predominant Neural Stem Cell Isolated from Postnatal and Adult Forebrain But Not Early Embryonic Forebrain Expresses GFAP

2003

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Mice devoid of the glial fibrillary acidic protein develop normally and are susceptible to scrapie prions

Cited by 243 publications

References 57 publications

Unaltered Secretion of β-Amyloid Precursor Protein in Gelatinase A (Matrix Metalloproteinase 2)-deficient Mice

Unaltered Secretion of β-Amyloid Precursor Protein in Gelatinase A (Matrix Metalloproteinase 2)-deficient Mice

Correlation of B-FABP and GFAP expression in malignant glioma

The Predominant Neural Stem Cell Isolated from Postnatal and Adult Forebrain But Not Early Embryonic Forebrain Expresses GFAP

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