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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.

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Related in: MedlinePlus

Sensorimotor functions of wild-type, E10+/βˆ’ and E10βˆ’/βˆ’ mice. (A) Mice devoid of tau exon 10 (E10βˆ’/βˆ’) showed no deficits in rotarod when they were 5–6Β months-old (E10+/+, n = 19; E10+/βˆ’, n = 17; E10βˆ’/βˆ’; n = 17), (B) but when compared to wild-type (E10+/+, p < 0.05) and E10+/βˆ’ (p < 0.01) their performance was impaired when they were 13–17Β months-old (E10+/+, n = 18; E10+/βˆ’, n = 16; E10βˆ’/βˆ’; n = 15). (C) 5–6Β months-old wild-type mice (E10+/+) were weaker than E10+/βˆ’ (p < 0.05: E10+/+, n = 9; E10+/βˆ’, n = 8; E10βˆ’/βˆ’; n = 8), (D) while 13–17Β months-old E10βˆ’/βˆ’ mice were weaker than E10+/βˆ’ (p < 0.05). *p < 0.05; **p < 0.01.
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Figure 3: Sensorimotor functions of wild-type, E10+/βˆ’ and E10βˆ’/βˆ’ mice. (A) Mice devoid of tau exon 10 (E10βˆ’/βˆ’) showed no deficits in rotarod when they were 5–6Β months-old (E10+/+, n = 19; E10+/βˆ’, n = 17; E10βˆ’/βˆ’; n = 17), (B) but when compared to wild-type (E10+/+, p < 0.05) and E10+/βˆ’ (p < 0.01) their performance was impaired when they were 13–17Β months-old (E10+/+, n = 18; E10+/βˆ’, n = 16; E10βˆ’/βˆ’; n = 15). (C) 5–6Β months-old wild-type mice (E10+/+) were weaker than E10+/βˆ’ (p < 0.05: E10+/+, n = 9; E10+/βˆ’, n = 8; E10βˆ’/βˆ’; n = 8), (D) while 13–17Β months-old E10βˆ’/βˆ’ mice were weaker than E10+/βˆ’ (p < 0.05). *p < 0.05; **p < 0.01.

Mentions: Subsequently, we aimed to investigate the physiological and functional role of exon 10 in tau. In previous reports, tau knockout mice developed sensorimotor dysfunctions due to loss of tau protein synthesis [3]. Cerebellum, which is implicated in balance and motor learning, develops at postnatal stages when 4R-tau is normally produced. We therefore examined whether partial or complete absence of exon 10 in tau led to sensorimotor anomalies in adult (5–6Β months) and middle-aged (13–17Β months) gene-manipulated mice. Rotarod and grip strength meter were used to assess sensorimotor dysfunctions. Genotype-dependent motor coordination dysfunction was not detected among adult mice (FigureΒ 3A, F(2,50) = 0.27; p = 0.76), while differences in rotarod performance were observed among middle-aged mice (F(2,46) = 4.34; p < 0.05). Post-hoc analyses showed that E10βˆ’/βˆ’ mice were impaired compared to E10+/+ (p < 0.05) and E10+/βˆ’ (p < 0.01, FigureΒ 3B). Similar results were found when the highest speed at which the animals remained on the rotarod was used as outcome measure (Additional file 1: Figure S2, F(2.46) = 5.05; p < 0.05). Post-hoc analyses revealed that the muscular strength of adult E10+/βˆ’ mice was superior to that of E10+/+ mice (FigureΒ 3C; p < 0.05). In contrast, middle-aged E10βˆ’/βˆ’ mice were weaker than E10+/βˆ’ (p < 0.05), but not E10+/+ mice (p = 0.10; F(2,45) = 2.43; FigureΒ 3D).


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)

Sensorimotor functions of wild-type, E10+/βˆ’ and E10βˆ’/βˆ’ mice. (A) Mice devoid of tau exon 10 (E10βˆ’/βˆ’) showed no deficits in rotarod when they were 5–6Β months-old (E10+/+, n = 19; E10+/βˆ’, n = 17; E10βˆ’/βˆ’; n = 17), (B) but when compared to wild-type (E10+/+, p < 0.05) and E10+/βˆ’ (p < 0.01) their performance was impaired when they were 13–17Β months-old (E10+/+, n = 18; E10+/βˆ’, n = 16; E10βˆ’/βˆ’; n = 15). (C) 5–6Β months-old wild-type mice (E10+/+) were weaker than E10+/βˆ’ (p < 0.05: E10+/+, n = 9; E10+/βˆ’, n = 8; E10βˆ’/βˆ’; n = 8), (D) while 13–17Β months-old E10βˆ’/βˆ’ mice were weaker than E10+/βˆ’ (p < 0.05). *p < 0.05; **p < 0.01.
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Figure 3: Sensorimotor functions of wild-type, E10+/βˆ’ and E10βˆ’/βˆ’ mice. (A) Mice devoid of tau exon 10 (E10βˆ’/βˆ’) showed no deficits in rotarod when they were 5–6Β months-old (E10+/+, n = 19; E10+/βˆ’, n = 17; E10βˆ’/βˆ’; n = 17), (B) but when compared to wild-type (E10+/+, p < 0.05) and E10+/βˆ’ (p < 0.01) their performance was impaired when they were 13–17Β months-old (E10+/+, n = 18; E10+/βˆ’, n = 16; E10βˆ’/βˆ’; n = 15). (C) 5–6Β months-old wild-type mice (E10+/+) were weaker than E10+/βˆ’ (p < 0.05: E10+/+, n = 9; E10+/βˆ’, n = 8; E10βˆ’/βˆ’; n = 8), (D) while 13–17Β months-old E10βˆ’/βˆ’ mice were weaker than E10+/βˆ’ (p < 0.05). *p < 0.05; **p < 0.01.
Mentions: Subsequently, we aimed to investigate the physiological and functional role of exon 10 in tau. In previous reports, tau knockout mice developed sensorimotor dysfunctions due to loss of tau protein synthesis [3]. Cerebellum, which is implicated in balance and motor learning, develops at postnatal stages when 4R-tau is normally produced. We therefore examined whether partial or complete absence of exon 10 in tau led to sensorimotor anomalies in adult (5–6Β months) and middle-aged (13–17Β months) gene-manipulated mice. Rotarod and grip strength meter were used to assess sensorimotor dysfunctions. Genotype-dependent motor coordination dysfunction was not detected among adult mice (FigureΒ 3A, F(2,50) = 0.27; p = 0.76), while differences in rotarod performance were observed among middle-aged mice (F(2,46) = 4.34; p < 0.05). Post-hoc analyses showed that E10βˆ’/βˆ’ mice were impaired compared to E10+/+ (p < 0.05) and E10+/βˆ’ (p < 0.01, FigureΒ 3B). Similar results were found when the highest speed at which the animals remained on the rotarod was used as outcome measure (Additional file 1: Figure S2, F(2.46) = 5.05; p < 0.05). Post-hoc analyses revealed that the muscular strength of adult E10+/βˆ’ mice was superior to that of E10+/+ mice (FigureΒ 3C; p < 0.05). In contrast, middle-aged E10βˆ’/βˆ’ mice were weaker than E10+/βˆ’ (p < 0.05), but not E10+/+ mice (p = 0.10; F(2,45) = 2.43; FigureΒ 3D).

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