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Lack of dystrophin protein Dp71 results in progressive cataract formation due to loss of fiber cell organization.

Fort PE, Darche M, Sahel JA, Rendon A, Tadayoni R - Mol. Vis. (2014)

Bottom Line: The role of Dp71 in fiber cells was also suggested by the progressive disorganization of the lens fibers, which was observed in the absence of Dp71 and demonstrated by irregular staining of the actin network and the aqueous channel AQP0.While its role in the retina has been well characterized, this study demonstrates for the first time the role played by Dp71 in a different ocular tissue: the crystalline lens.It primarily demonstrates the role that Dp71 plays in the maintenance of the integrity of the secondary lens fibers.

View Article: PubMed Central - PubMed

Affiliation: Institut de la Vision/INSERM/UPMC, Univ Paris 06/CNRS/CHNO des Quinze-Vingts, Paris, France ; Kellogg Eye Center, Departments of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI.

ABSTRACT

Purpose: Dp71 is the main product of the Duchenne muscular dystrophy (DMD) gene in the central nervous system. While studying the impact of its absence on retinal functions, we discovered that mice lacking Dp71 also developed a progressive opacification of the crystalline lens. The purpose of this study was to perform a detailed characterization of the cataract formation in Dp71 knockout (KO-Dp71) mice.

Methods: Cataract formations in KO-Dp71 mice and wild-type (wt) littermates were assessed in vivo by slit-lamp examination and ex vivo by histological analysis as a function of aging. The expression and cellular localization of the DMD gene products were monitored by western blot and immunohistochemical analysis. Fiber cell integrity was assessed by analyzing the actin cytoskeleton as well as the expression of aquaporin-0 (AQP0).

Results: As expected, a slit-lamp examination revealed that only one of the 20 tested wt animals presented with a mild opacification of the lens and only at the most advanced age. However, a lack of Dp71 was associated with a 40% incidence of cataracts as early as 2 months of age, which progressively increased to full penetrance by 7 months. A subsequent histological analysis revealed an alteration in the structures of the lenses of KO-Dp71 mice that correlated with the severity of the lens opacity. An analysis of the expression of the different dystrophin gene products revealed that Dp71 was the major DMD gene product expressed in the lens, especially in fiber cells. The role of Dp71 in fiber cells was also suggested by the progressive disorganization of the lens fibers, which was observed in the absence of Dp71 and demonstrated by irregular staining of the actin network and the aqueous channel AQP0.

Conclusions: While its role in the retina has been well characterized, this study demonstrates for the first time the role played by Dp71 in a different ocular tissue: the crystalline lens. It primarily demonstrates the role that Dp71 plays in the maintenance of the integrity of the secondary lens fibers.

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The absence of Dp71 leads to a profound disorganization of the actin filaments. Images of the F-actin network (green) and the cell nuclei (blue) at the level of the epithelium of 9-month-old wt (A-B) and KO-Dp71 mice (C-D). Similar to the results obtained by immunostaining, the network of actin filaments in lens epithelial cells was not different in wt (A-B) versus KO-Dp71 (C-D) mice. However, images of the actin network deep within the lens demonstrate subtle but noticeable changes in the lens fiber cell region at 3 months (E: wt-F:KO-Dp71), as well as changes that were exacerbated with aging, as demonstrated at 9 months (G: wt-H:KO-Dp71). Scale bar: 300 μm.
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f6: The absence of Dp71 leads to a profound disorganization of the actin filaments. Images of the F-actin network (green) and the cell nuclei (blue) at the level of the epithelium of 9-month-old wt (A-B) and KO-Dp71 mice (C-D). Similar to the results obtained by immunostaining, the network of actin filaments in lens epithelial cells was not different in wt (A-B) versus KO-Dp71 (C-D) mice. However, images of the actin network deep within the lens demonstrate subtle but noticeable changes in the lens fiber cell region at 3 months (E: wt-F:KO-Dp71), as well as changes that were exacerbated with aging, as demonstrated at 9 months (G: wt-H:KO-Dp71). Scale bar: 300 μm.

Mentions: Consistent with the limited impact of the absence of Dp71 observed through other methods, an analysis of the actin filaments in the superficial epithelial cells did not reveal any profound alterations in KO-Dp71 mice, even at 9 months of age (Figures 6A–D). Interestingly, however, consistent with the alterations observed through histology and immunostaining, the actin filaments were noticeably disorganized starting at 3 months (Figure 6F), an effect that was enhanced at 9 months of age (Figure 6H).


Lack of dystrophin protein Dp71 results in progressive cataract formation due to loss of fiber cell organization.

Fort PE, Darche M, Sahel JA, Rendon A, Tadayoni R - Mol. Vis. (2014)

The absence of Dp71 leads to a profound disorganization of the actin filaments. Images of the F-actin network (green) and the cell nuclei (blue) at the level of the epithelium of 9-month-old wt (A-B) and KO-Dp71 mice (C-D). Similar to the results obtained by immunostaining, the network of actin filaments in lens epithelial cells was not different in wt (A-B) versus KO-Dp71 (C-D) mice. However, images of the actin network deep within the lens demonstrate subtle but noticeable changes in the lens fiber cell region at 3 months (E: wt-F:KO-Dp71), as well as changes that were exacerbated with aging, as demonstrated at 9 months (G: wt-H:KO-Dp71). Scale bar: 300 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4225142&req=5

f6: The absence of Dp71 leads to a profound disorganization of the actin filaments. Images of the F-actin network (green) and the cell nuclei (blue) at the level of the epithelium of 9-month-old wt (A-B) and KO-Dp71 mice (C-D). Similar to the results obtained by immunostaining, the network of actin filaments in lens epithelial cells was not different in wt (A-B) versus KO-Dp71 (C-D) mice. However, images of the actin network deep within the lens demonstrate subtle but noticeable changes in the lens fiber cell region at 3 months (E: wt-F:KO-Dp71), as well as changes that were exacerbated with aging, as demonstrated at 9 months (G: wt-H:KO-Dp71). Scale bar: 300 μm.
Mentions: Consistent with the limited impact of the absence of Dp71 observed through other methods, an analysis of the actin filaments in the superficial epithelial cells did not reveal any profound alterations in KO-Dp71 mice, even at 9 months of age (Figures 6A–D). Interestingly, however, consistent with the alterations observed through histology and immunostaining, the actin filaments were noticeably disorganized starting at 3 months (Figure 6F), an effect that was enhanced at 9 months of age (Figure 6H).

Bottom Line: The role of Dp71 in fiber cells was also suggested by the progressive disorganization of the lens fibers, which was observed in the absence of Dp71 and demonstrated by irregular staining of the actin network and the aqueous channel AQP0.While its role in the retina has been well characterized, this study demonstrates for the first time the role played by Dp71 in a different ocular tissue: the crystalline lens.It primarily demonstrates the role that Dp71 plays in the maintenance of the integrity of the secondary lens fibers.

View Article: PubMed Central - PubMed

Affiliation: Institut de la Vision/INSERM/UPMC, Univ Paris 06/CNRS/CHNO des Quinze-Vingts, Paris, France ; Kellogg Eye Center, Departments of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI.

ABSTRACT

Purpose: Dp71 is the main product of the Duchenne muscular dystrophy (DMD) gene in the central nervous system. While studying the impact of its absence on retinal functions, we discovered that mice lacking Dp71 also developed a progressive opacification of the crystalline lens. The purpose of this study was to perform a detailed characterization of the cataract formation in Dp71 knockout (KO-Dp71) mice.

Methods: Cataract formations in KO-Dp71 mice and wild-type (wt) littermates were assessed in vivo by slit-lamp examination and ex vivo by histological analysis as a function of aging. The expression and cellular localization of the DMD gene products were monitored by western blot and immunohistochemical analysis. Fiber cell integrity was assessed by analyzing the actin cytoskeleton as well as the expression of aquaporin-0 (AQP0).

Results: As expected, a slit-lamp examination revealed that only one of the 20 tested wt animals presented with a mild opacification of the lens and only at the most advanced age. However, a lack of Dp71 was associated with a 40% incidence of cataracts as early as 2 months of age, which progressively increased to full penetrance by 7 months. A subsequent histological analysis revealed an alteration in the structures of the lenses of KO-Dp71 mice that correlated with the severity of the lens opacity. An analysis of the expression of the different dystrophin gene products revealed that Dp71 was the major DMD gene product expressed in the lens, especially in fiber cells. The role of Dp71 in fiber cells was also suggested by the progressive disorganization of the lens fibers, which was observed in the absence of Dp71 and demonstrated by irregular staining of the actin network and the aqueous channel AQP0.

Conclusions: While its role in the retina has been well characterized, this study demonstrates for the first time the role played by Dp71 in a different ocular tissue: the crystalline lens. It primarily demonstrates the role that Dp71 plays in the maintenance of the integrity of the secondary lens fibers.

Show MeSH
Related in: MedlinePlus