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Targeted ablation of NrCAM or ankyrin-B results in disorganized lens fibers leading to cataract formation.

Moré MI, Kirsch FP, Rathjen FG - J. Cell Biol. (2001)

Bottom Line: The NgCAM-related cell adhesion molecule (NrCAM) is an immunoglobulin superfamily member of the L1 subgroup that interacts intracellularly with ankyrins.The disorganization of fiber cells becomes histologically distinct during late embryonic development and includes abnormalities of the cytoskeleton and of connexin50-containing gap junctions.Also, these studies provide genetic evidence of an interaction between NrCAM and ankyrin-B.

View Article: PubMed Central - PubMed

Affiliation: Max-Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, D-13092 Berlin, Germany.

ABSTRACT
The NgCAM-related cell adhesion molecule (NrCAM) is an immunoglobulin superfamily member of the L1 subgroup that interacts intracellularly with ankyrins. We reveal that the absence of NrCAM causes the formation of mature cataracts in the mouse, whereas significant pathfinding errors of commissural axons at the midline of the spinal cord or of proprioceptive axon collaterals are not detected. Cataracts, the most common cause of visual impairment, are generated in NrCAM-deficient mice by a disorganization of lens fibers, followed by cellular disintegration and accumulation of cellular debris. The disorganization of fiber cells becomes histologically distinct during late embryonic development and includes abnormalities of the cytoskeleton and of connexin50-containing gap junctions. Furthermore, analysis of lenses of ankyrin-B mutant mice also reveals a disorganization of lens fibers at postnatal day 1, indistinguishable from that generated by the absence of NrCAM, indicating that NrCAM and ankyrin-B are required to maintain contact between lens fiber cells. Also, these studies provide genetic evidence of an interaction between NrCAM and ankyrin-B.

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Cataract histology of NrCAM-deficient mice. From the emergence of secondary lens fibers onwards, NrCAM-deficient lens fibers develop a rounded instead of elongated shape, indicating loss of cell–cell contact. The phenotype is progressive and leads to a disintegration of lens fibers and accumulation of cellular debris. (a) NrCAM−/− E14.5 longitudinal section, HE stained. (b and c) NrCAM−/− E18 longitudinal sections, HE stained. (d) NrCAM−/− P12 noncentral longitudinal section, anterior region, TB stained. (c–k) Positions of sections in the lens are indicated in l. (e) 2-mo-old wild-type posterior region in noncentral longitudinal section, HE stained. (f) Same as e, but with NrCAM−/−. (g–h) 2-mo-old NrCAM−/− central longitudinal section, TB stained. (g) One-third of the way to the center side-front region. (h) Half-way to the center posterior region. (i–k) 8-mo-old NrCAM−/− lens in longitudinal noncentral section, HE stained. (i) Marginal region. (j) Anterior region. (k) Posterior region. *Cellular debris; arrowheads, intensely stained rounded cell; arrows, examples of secondary fiber cells in the process of rounding up due to contact loss of neighboring cells; open arrows, cells in the process of disintegration.
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fig4: Cataract histology of NrCAM-deficient mice. From the emergence of secondary lens fibers onwards, NrCAM-deficient lens fibers develop a rounded instead of elongated shape, indicating loss of cell–cell contact. The phenotype is progressive and leads to a disintegration of lens fibers and accumulation of cellular debris. (a) NrCAM−/− E14.5 longitudinal section, HE stained. (b and c) NrCAM−/− E18 longitudinal sections, HE stained. (d) NrCAM−/− P12 noncentral longitudinal section, anterior region, TB stained. (c–k) Positions of sections in the lens are indicated in l. (e) 2-mo-old wild-type posterior region in noncentral longitudinal section, HE stained. (f) Same as e, but with NrCAM−/−. (g–h) 2-mo-old NrCAM−/− central longitudinal section, TB stained. (g) One-third of the way to the center side-front region. (h) Half-way to the center posterior region. (i–k) 8-mo-old NrCAM−/− lens in longitudinal noncentral section, HE stained. (i) Marginal region. (j) Anterior region. (k) Posterior region. *Cellular debris; arrowheads, intensely stained rounded cell; arrows, examples of secondary fiber cells in the process of rounding up due to contact loss of neighboring cells; open arrows, cells in the process of disintegration.

Mentions: To begin to understand the importance of NrCAM for the development and maintenance of a functional translucent lens, we investigated lenses of NrCAM−/− mice of different stages by standard histological methods. In mouse lenses of E14.5 embryos that consist predominantly of primary lens fibers, no significant morphological changes were observed in the NrCAM mutant (Fig. 4 a). At E18, secondary lens fibers have developed. Even though there are roundish large-appearing cells especially at the anterior pole close to the suture in the mutant, most of the fiber cells remain ordered in the transition zone as in wild type (Fig. 4, b and c). Also, at P12 there are many fiber cells remaining in a somewhat ordered context, in particular in the periphery, but the number of rounded disoriented cells among the secondary lens fibers increases towards the nucleus of the lens (Fig. 4 d). By 2 mo, the regular wild-type pattern (Fig. 4 e) of cross-sectioned secondary lens fibers is severely disturbed in the NrCAM−/− lens (Fig. 4 f), as shown here for the region around the posterior pole. The cell shape and arrangement is still most ordered for the cells that have migrated inwards from the epithelium more recently (Fig. 4 g, upper right). But even among these cells, there are some cells that start to round up, becoming shorter and thicker (arrow). Other cells have lost their integrity completely, creating distinct zones of cellular debris (Fig. 4 g, *). Persisting cells are intensely stained, rounded, and have lost their orientation (Fig. 4 g, arrowhead). At regions half-way to the center of the lens, especially at the posterior region, we observe deformed cells that have lost contact to each other completely (Fig. 4 h).


Targeted ablation of NrCAM or ankyrin-B results in disorganized lens fibers leading to cataract formation.

Moré MI, Kirsch FP, Rathjen FG - J. Cell Biol. (2001)

Cataract histology of NrCAM-deficient mice. From the emergence of secondary lens fibers onwards, NrCAM-deficient lens fibers develop a rounded instead of elongated shape, indicating loss of cell–cell contact. The phenotype is progressive and leads to a disintegration of lens fibers and accumulation of cellular debris. (a) NrCAM−/− E14.5 longitudinal section, HE stained. (b and c) NrCAM−/− E18 longitudinal sections, HE stained. (d) NrCAM−/− P12 noncentral longitudinal section, anterior region, TB stained. (c–k) Positions of sections in the lens are indicated in l. (e) 2-mo-old wild-type posterior region in noncentral longitudinal section, HE stained. (f) Same as e, but with NrCAM−/−. (g–h) 2-mo-old NrCAM−/− central longitudinal section, TB stained. (g) One-third of the way to the center side-front region. (h) Half-way to the center posterior region. (i–k) 8-mo-old NrCAM−/− lens in longitudinal noncentral section, HE stained. (i) Marginal region. (j) Anterior region. (k) Posterior region. *Cellular debris; arrowheads, intensely stained rounded cell; arrows, examples of secondary fiber cells in the process of rounding up due to contact loss of neighboring cells; open arrows, cells in the process of disintegration.
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Related In: Results  -  Collection

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fig4: Cataract histology of NrCAM-deficient mice. From the emergence of secondary lens fibers onwards, NrCAM-deficient lens fibers develop a rounded instead of elongated shape, indicating loss of cell–cell contact. The phenotype is progressive and leads to a disintegration of lens fibers and accumulation of cellular debris. (a) NrCAM−/− E14.5 longitudinal section, HE stained. (b and c) NrCAM−/− E18 longitudinal sections, HE stained. (d) NrCAM−/− P12 noncentral longitudinal section, anterior region, TB stained. (c–k) Positions of sections in the lens are indicated in l. (e) 2-mo-old wild-type posterior region in noncentral longitudinal section, HE stained. (f) Same as e, but with NrCAM−/−. (g–h) 2-mo-old NrCAM−/− central longitudinal section, TB stained. (g) One-third of the way to the center side-front region. (h) Half-way to the center posterior region. (i–k) 8-mo-old NrCAM−/− lens in longitudinal noncentral section, HE stained. (i) Marginal region. (j) Anterior region. (k) Posterior region. *Cellular debris; arrowheads, intensely stained rounded cell; arrows, examples of secondary fiber cells in the process of rounding up due to contact loss of neighboring cells; open arrows, cells in the process of disintegration.
Mentions: To begin to understand the importance of NrCAM for the development and maintenance of a functional translucent lens, we investigated lenses of NrCAM−/− mice of different stages by standard histological methods. In mouse lenses of E14.5 embryos that consist predominantly of primary lens fibers, no significant morphological changes were observed in the NrCAM mutant (Fig. 4 a). At E18, secondary lens fibers have developed. Even though there are roundish large-appearing cells especially at the anterior pole close to the suture in the mutant, most of the fiber cells remain ordered in the transition zone as in wild type (Fig. 4, b and c). Also, at P12 there are many fiber cells remaining in a somewhat ordered context, in particular in the periphery, but the number of rounded disoriented cells among the secondary lens fibers increases towards the nucleus of the lens (Fig. 4 d). By 2 mo, the regular wild-type pattern (Fig. 4 e) of cross-sectioned secondary lens fibers is severely disturbed in the NrCAM−/− lens (Fig. 4 f), as shown here for the region around the posterior pole. The cell shape and arrangement is still most ordered for the cells that have migrated inwards from the epithelium more recently (Fig. 4 g, upper right). But even among these cells, there are some cells that start to round up, becoming shorter and thicker (arrow). Other cells have lost their integrity completely, creating distinct zones of cellular debris (Fig. 4 g, *). Persisting cells are intensely stained, rounded, and have lost their orientation (Fig. 4 g, arrowhead). At regions half-way to the center of the lens, especially at the posterior region, we observe deformed cells that have lost contact to each other completely (Fig. 4 h).

Bottom Line: The NgCAM-related cell adhesion molecule (NrCAM) is an immunoglobulin superfamily member of the L1 subgroup that interacts intracellularly with ankyrins.The disorganization of fiber cells becomes histologically distinct during late embryonic development and includes abnormalities of the cytoskeleton and of connexin50-containing gap junctions.Also, these studies provide genetic evidence of an interaction between NrCAM and ankyrin-B.

View Article: PubMed Central - PubMed

Affiliation: Max-Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, D-13092 Berlin, Germany.

ABSTRACT
The NgCAM-related cell adhesion molecule (NrCAM) is an immunoglobulin superfamily member of the L1 subgroup that interacts intracellularly with ankyrins. We reveal that the absence of NrCAM causes the formation of mature cataracts in the mouse, whereas significant pathfinding errors of commissural axons at the midline of the spinal cord or of proprioceptive axon collaterals are not detected. Cataracts, the most common cause of visual impairment, are generated in NrCAM-deficient mice by a disorganization of lens fibers, followed by cellular disintegration and accumulation of cellular debris. The disorganization of fiber cells becomes histologically distinct during late embryonic development and includes abnormalities of the cytoskeleton and of connexin50-containing gap junctions. Furthermore, analysis of lenses of ankyrin-B mutant mice also reveals a disorganization of lens fibers at postnatal day 1, indistinguishable from that generated by the absence of NrCAM, indicating that NrCAM and ankyrin-B are required to maintain contact between lens fiber cells. Also, these studies provide genetic evidence of an interaction between NrCAM and ankyrin-B.

Show MeSH
Related in: MedlinePlus