Limits...
Lack of exon 10 in the murine tau gene results in mild sensorimotor defects with aging.

Gumucio A, Lannfelt L, Nilsson LN - BMC Neurosci (2013)

Bottom Line: Cognitive abilities or anxiety-like behaviours did not depend on exon 10 in tau, and neither pathological inclusions nor gene-dependent morphological abnormalities were found.Ablation of exon 10 in the murine tau gene alters alternative splicing and tau protein synthesis which results in mild sensorimotor phenotypes with aging.Presumably related microtubule-stabilizing genes rescue other functions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Public Health and Caring Sciences, Rudbeck Laboratory, Uppsala University, SE-75185 Uppsala, Sweden. Lars.Nilsson@medisin.uio.no.

ABSTRACT

Background: Complex species-specific, developmental- and tissue-dependent mechanisms regulate alternative splicing of tau, thereby diversifying tau protein synthesis. The functional role of alternative splicing of tau e.g. exon 10 has never been examined in vivo, although genetic studies suggest that it is important to neurodegenerative disease.

Results: Gene-targeting was used to delete exon 10 in murine tau on both alleles (E10-/-) to study its functional role. Moreover, mice devoid of exon 10 (E10+/-) on one allele were generated to investigate the effects of 1:1 balanced expression of 4R-/3R-tau protein, since equal amounts of 4R-/3R-tau protein are synthesized in human brain. Middle-aged E10-/- mice displayed sensorimotor disturbances in the rotarod when compared to age-matched E10+/- and wild-type mice, and their muscular grip strength was less than that of E10+/- mice. The performance of E10+/- mice and wild-type mice (E10+/+) was similar in sensorimotor tests. Cognitive abilities or anxiety-like behaviours did not depend on exon 10 in tau, and neither pathological inclusions nor gene-dependent morphological abnormalities were found.

Conclusion: Ablation of exon 10 in the murine tau gene alters alternative splicing and tau protein synthesis which results in mild sensorimotor phenotypes with aging. Presumably related microtubule-stabilizing genes rescue other functions.

Show MeSH

Related in: MedlinePlus

Gross morphology of wild-type, E10+/− and E10−/− mice. Coronal sections from 12 months-old mice which were stained with hematoxylin and Luxol fast blue dyes. There were no apparent genotype-dependent differences in (A-F) forebrain, (G-I) hind brain or (J-O) spinal cord. Scale bar measures 500 μm (A-C, G-I), 250 μm (J-L), 125 μm (D-F) and 63 μm (M-O).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4222861&req=5

Figure 6: Gross morphology of wild-type, E10+/− and E10−/− mice. Coronal sections from 12 months-old mice which were stained with hematoxylin and Luxol fast blue dyes. There were no apparent genotype-dependent differences in (A-F) forebrain, (G-I) hind brain or (J-O) spinal cord. Scale bar measures 500 μm (A-C, G-I), 250 μm (J-L), 125 μm (D-F) and 63 μm (M-O).

Mentions: Brains of 12 months-old wild-type (E10+/+), E10+/− and E10−/− mice were examined for major structural changes. Sections were stained with hematoxylin and luxol fast blue dyes, but we did not find any genotype-dependent differences in the forebrain, cerebellum or spinal cord (Figure 6). The astroglial marker, glial fibrillary acidic-protein (GFAP) was used as a rather unspecific sensor of abnormalities in brain tissue. However, we did not find any differences between the mice (Figure 7). Similarly, there were no genotype-dependent differences in GFAP-staining in cerebellar tissue (data not shown) and no macroscopic differences of whole brain (Additional file 1: Figure S4). We were unable to find any evidence of tau aggregation in the brains of E10+/− or E10−/− mice (data not shown).


Lack of exon 10 in the murine tau gene results in mild sensorimotor defects with aging.

Gumucio A, Lannfelt L, Nilsson LN - BMC Neurosci (2013)

Gross morphology of wild-type, E10+/− and E10−/− mice. Coronal sections from 12 months-old mice which were stained with hematoxylin and Luxol fast blue dyes. There were no apparent genotype-dependent differences in (A-F) forebrain, (G-I) hind brain or (J-O) spinal cord. Scale bar measures 500 μm (A-C, G-I), 250 μm (J-L), 125 μm (D-F) and 63 μm (M-O).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222861&req=5

Figure 6: Gross morphology of wild-type, E10+/− and E10−/− mice. Coronal sections from 12 months-old mice which were stained with hematoxylin and Luxol fast blue dyes. There were no apparent genotype-dependent differences in (A-F) forebrain, (G-I) hind brain or (J-O) spinal cord. Scale bar measures 500 μm (A-C, G-I), 250 μm (J-L), 125 μm (D-F) and 63 μm (M-O).
Mentions: Brains of 12 months-old wild-type (E10+/+), E10+/− and E10−/− mice were examined for major structural changes. Sections were stained with hematoxylin and luxol fast blue dyes, but we did not find any genotype-dependent differences in the forebrain, cerebellum or spinal cord (Figure 6). The astroglial marker, glial fibrillary acidic-protein (GFAP) was used as a rather unspecific sensor of abnormalities in brain tissue. However, we did not find any differences between the mice (Figure 7). Similarly, there were no genotype-dependent differences in GFAP-staining in cerebellar tissue (data not shown) and no macroscopic differences of whole brain (Additional file 1: Figure S4). We were unable to find any evidence of tau aggregation in the brains of E10+/− or E10−/− mice (data not shown).

Bottom Line: Cognitive abilities or anxiety-like behaviours did not depend on exon 10 in tau, and neither pathological inclusions nor gene-dependent morphological abnormalities were found.Ablation of exon 10 in the murine tau gene alters alternative splicing and tau protein synthesis which results in mild sensorimotor phenotypes with aging.Presumably related microtubule-stabilizing genes rescue other functions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Public Health and Caring Sciences, Rudbeck Laboratory, Uppsala University, SE-75185 Uppsala, Sweden. Lars.Nilsson@medisin.uio.no.

ABSTRACT

Background: Complex species-specific, developmental- and tissue-dependent mechanisms regulate alternative splicing of tau, thereby diversifying tau protein synthesis. The functional role of alternative splicing of tau e.g. exon 10 has never been examined in vivo, although genetic studies suggest that it is important to neurodegenerative disease.

Results: Gene-targeting was used to delete exon 10 in murine tau on both alleles (E10-/-) to study its functional role. Moreover, mice devoid of exon 10 (E10+/-) on one allele were generated to investigate the effects of 1:1 balanced expression of 4R-/3R-tau protein, since equal amounts of 4R-/3R-tau protein are synthesized in human brain. Middle-aged E10-/- mice displayed sensorimotor disturbances in the rotarod when compared to age-matched E10+/- and wild-type mice, and their muscular grip strength was less than that of E10+/- mice. The performance of E10+/- mice and wild-type mice (E10+/+) was similar in sensorimotor tests. Cognitive abilities or anxiety-like behaviours did not depend on exon 10 in tau, and neither pathological inclusions nor gene-dependent morphological abnormalities were found.

Conclusion: Ablation of exon 10 in the murine tau gene alters alternative splicing and tau protein synthesis which results in mild sensorimotor phenotypes with aging. Presumably related microtubule-stabilizing genes rescue other functions.

Show MeSH
Related in: MedlinePlus