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Hereditary Cataracts in Deer Mice (Peromyscus Maniculatus)
HEREDITARY CATARACTS IN DEER MICE (PEROMYSCUS MANICULATUS) R O B E R T P. B U R N S , M.D.,
AND L Y N E T T E F E E N E Y , P H . D .
Portland, Oregon
necessary. 3 This decreases the frequency of the autosomal-recessive trait. Cataractous development can be pre dicted in deer mice born with clear lenses, because syndactyly of the middle toes of the hind feet occurs in animals destined to develop cataracts, and can be identified at 13 to 14 days of age. Some times the third and fourth toes on the front feet are fused, but this is less pre dictable for cataracts than syndactyly of the hind feet. The coincidence of the two defects is probably due to either gene linkage or pleiotropic effects of a single gene. Animals without toe fusion do not appear to inherit cataracts and are consid ered normal in this study.
It is a pleasure to dedicate this work to Michael Hogan. Teacher, friend, and in vestigator, he has been a leader in the integration of structure and function in the eye. This is the first report of predictable hereditary cataracts in the Peromyscus maniculatus (peros-maimed; mus-mouse) or deer mouse, a rodent found throughout the United States.* The cataract resem bles lens opacities that occur after acute metabolic insults or those that develop slowly during the aging process. We feel that this progressive lens opacification may be a model for the study of senile cataract. We studied a colony of deer mice for one year. Their cataracts are inherited as an autosomal-recessive trait. At first, cata racts were visible at 3 years of age. (The maximum life span of deer mice is 8 years). By selective breeding, the fre quency of cataracts increased, and be came visible at 2 months to 1 year of age. Brother and sister breeding attempts were carried out, but inbreeding decreased the frequency of mating in litters, so periodic outbreeding into unaffected deer mice is
M A T E R I A L S AND M E T H O D S
These Peromyscus were first studied by R. R. Huestis, Ph.D., University of Oregon, Eugene, Ore gon. While examining the inheritance of iris color, he noted that some of the animals had cataracts.1 A further hereditary defect includes neonatal jaundice that resembles hereditary spherocytosis in man.2 We obtained a colony through Ruth Anderson, Ph.D., Division of Immunology, University of Oregon Health Sciences Center, Portland, Oregon. From the John E. Weeks Memorial Laboratory of Ophthalmology, University of Oregon Medical School, Portland, Oregon. This study was supported in part by grants EY00753 and EY00715, and Re search to Prevent Blindness, Inc. Reprint requests to Robert P. Burns, M.D., John E. Weeks Memorial Laboratory of Ophthalmology, University of Oregon Medical School, Portland OR 97201.
Animals were maintained in animal quarters for one year. Deer mice breed by 6 weeks of age, and usually have two to four in a litter. The female deer mouse can breed the first day after giving birth to a litter. Sibling mating was encouraged, as was back breeding to the parent. We examined the animals with a HaagStreit 900 slit lamp. The deer mouse lens was large and the eyes dilated well with cycloplegics. Animals were anesthetized with methoxyflurane for slit-lamp pho tography. Selected animals were killed with an overdose of anesthetic. Whole heads of animals younger than 10 days old were fixed in 10% neutral formalin. After the eyelids opened at about 14 days, eyes were enucleated and placed in either 10% formalin for paraffin embedding or a 2% paraformaldehyde-1% glutaraldehyde mixture for plastic embedding. Some lenses were dissected from the globe be fore fixation, and others were dissected after fixation and before embedding. Par-
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affin sections were stained with hematoxylin and eosin. Epoxy sections were stained with toluidine blue-borax stain. RESULTS
Biomicroscopy—The head and fused toes of a deer mouse with white lenses are shown in Figures 1 and 2. The biomicroscopic findings varied from clear lens with normal Y sutures, to a diffuse nonlocalized haziness in the lens, to anterior subcapsular and posterior subcapsular opacities (Fig. 3, left and center), to a complete mature white cataract (Fig. 3, right). Wrinkled hypermature cataracts with iritis and atrophy of the entire globe occurred in the final stages of opacification. Iris anomalies also occurred. We noted colobomas of the iris in some ani mals with cataracts. Irides occasionally appeared atrophic with a hypermature cataract. Histology—Biomicroscopically, clear lenses from presumably normal deer mice with normal toes were histologically sim ilar to house mice 4 (Figs. 4 and 5). The lens in a 6- to 10-day-old deer mouse was round and filled the ocular cavity. The ciliary body and iris were rudimentary and a tunica vasculosa lentis was present. The lens bow contained many nuclei that spread deep and toward the anterior pole.
Fig. 1 (Burns and Feeney). Adult deer mouse has bilateral cataracts.
Fig. 2 (Burns and Feeney). Fused third and fourth toes (arrows) of the hind feet of a deer mouse.
The lens capsule was thin and zonular fibers were not visible. In plasticembedded sections, light and dark cells were scattered throughout the bow region (Fig. 6). We do not know whether these are indications of early disease or if more subtle abnormalities are present. At 25 days of age, about ten days after the eyelids opened, the lens appeared similar to a normal adult lens. There were fewer nuclei in the bow and the tunica vasculosa lentis disappeared. The lens was more lenticular but still occupied most of the eye. There was little differ ence in the 25-day-old specimen and a 2.5-year-old specimen from a deer mouse that had no fused toes and was not expect ed to develop a cataract. Pathology—The earliest pathologic changes in deer mice with fused toes that should have developed cataracts were vacuolation in and near the nuclei just inside the lens bow at the equator (Figs. 7 and 8). These cells at the equator of the lens, that are differentiating from anterior epithelium into lens fibers, seem to be the morphologic site of the initial pathology (Fig. 9). The equatorial cells of the lens migrat ed posteriorly under the lens capsule in the animals that developed posterior sub capsular cataracts (Fig. 10). The basal
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Fig. 3 (Burns and Feeney). Left, Slit-lamp photograph of a young adult deer mouse showing a posterior subcapsular cataract. Slit beam passes through cornea (C), iris (I), anterior lens surface (L), and cataract on posterior lens. Center, Front view, slit-lamp photograph of central posterior subcapsular cataract with an uneven, whorled appearance. Pupil is widely dilated; L indicates lens. Right, Slit-lamp photograph of a mature cataract. ends of the superficial cortical cells (that is, the posterior subcapsular lens fibers) had striations and disruptions in
paraffin-embedded sections (Fig. 11, left). The same specimen, embedded in plastic, had a different morphology: the most su-
Fig. 4 (Burns and Feeney.) Coronal section through the head of a 6-day-old deer mouse showing normal histology. Eyelids are still fused; cornea (C), lens (L), and retina (R) (paraffin, hematoxylin and eosin, x32).
Fig. 5 (Burns and Feeney). Section through lens equator in a 6-day-old normal lens showing distri bution of nuclei at the bow (B) (paraffin, hematoxy lin and eosin, x 150).
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Fig. 7 (Burns and Feeney). Clear lens by slit lamp in infant deer mouse with fused toes. Note vacuolization of superficial fibers just anterior to the bow (arrow) (plastic, toluidine blue, x77).
perficial cells were swollen and irregular, whereas underlying cells appeared dense and shrunken (Fig. 11, right). Large epithelioid round cells collected in the posterior subcapsular region in plaques, similar to cells described as "bladder" or "Wedl" cells 5 in human cataracts (Fig. 12). The anterior and pos terior poles of the same lens showed a large posterior subcapsular cataract but a relatively normal anterior surface (Fig. 13). However, the nuclei of the epithelial cells in the anterior lens appeared some what pyknotic. The anterior cortex in some lenses showed degeneration of superficial lens Fig. 6 (Burns and Feeney). Montage of lens equa tor in a normal infant deer mouse. Note normal appearance of epithelium and superficial lens fibers; T indicates tunica vasculosa lentis (plastic, toluidine blue, x420).
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Fig. 8 (Burns and Feeney). Enlargement of a portion of Figure 7. Note vacuolization near nuclei at the lens bow (plastic, toluidine blue, xlOO). fibers with pooling of the cytoplasmic protein into globules, while the overlying epithelium appeared relatively unaffect ed (Fig. 14). Proliferation of anterior epi thelium did not occur. As anterior cortical
Fig. 9 (Burns and Feeney). Montage of equatorial region of adult hazy lens. Compare the abnormali ties in spacing of nuclei (thin arrows) and in density of newly formed lens fibers (thick arrows) with those of normal lens in Figure 6. (Dots are an artifact of uneven staining.) Enclosed area is enlarged in inset (x250). Inset, Note dense cytoplasm of several ab normal lens fibers (arrows) (plastic, toluidine blue, X420).
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Fig. 10 (Burns and Feeney). Adult with hazy lens by slit lamp. Nuclei lie in several clusters at abnor mally posterior subcapsular sites (arrows) (paraffin, hematoxylin and eosin, x38).
opacities developed, the rest of the lens was obscured, and slit-lamp assessment of other abnormalities in these eyes was impossible. After cataracts developed in the super ficial cortex, either anteriorly or posterior ly, the lens nuclei disappeared with de velopment of a total cataract (Fig. 15). Wrinkling of the capsule, causing a small er lens, presumably resulted from a loss of protein through the lens capsule (Fig. 15). Inflammation in either the anterior or posterior chambers of the eye occasional ly occurred, with attraction of macrophages (Fig. 15, bottom), that eventually transformed into fibrocytes. Iris atrophy and retinal detachment occasionally en-
Fig. 11 (Burns and Feeney). Left, Posterior sutun area of same lens as in Figure 10- (paraffin, hematox ylin and eosin, x250). Right, Posterior suture area o fellow lens embedded in plastic. Note irregularitie; of superficial cells and various densities of deepe cells (plastic, toluidine blue, x250).
Fig. 12 (Burns and Feeney). Posterior subcapsuk cataract. Note epithelioid cells (paraffin, hematoxy lin and eosin x42).
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Fig. 14 (Burns and Feeney). Anterior cortical cataract (paraffin, hematoxylin and eosin, x38).
sued, as observed in human hypermature cataract. DISCUSSION
Although there are many ways to pro duce experimental cataracts, "none of these has yet offered a definite clue to the intimate mechanism involved in the oc currence of the usual lenticular opacities in man." 6 Spontaneously developing cat aracts provide an opportunity to study the biochemical and morphologic sequence of events leading to opacification. Hereditary cataracts in the house mouse (Mas musculus) have been de scribed. 7 These cataracts are visible by the 25th postnatal day and may be detect ed histologically in prenatal lenses. Vari ous defects in the morphogenesis and maturation of the lens cells have been described in mice. In the Fraser cataract strain, abnormalities in cells of the invaginating lens vesicle have been reported. 8 Many later steps in lens cell differen tiation are also abnormal, such as irreg ularities in cellular elongation, leakage
Fig. 13 (Burns and Feeney). Top, Anterior surface of eye whose slit-lamp appearance is shown in Figure 3, left. Nuclei (arrow) are somewhat pyknotic and resemble those about to undergo dissolution in the lens bow as they are displaced deeper into lens cortex (plastic, toluidine blue, x240). Bottom, Pos terior subcapsular cataract. Irregularities produced by various depths of epithelioid cell plaques corre spond to various densities of the cataract shown in Figure 3, left and center (paraffin, plastic, toluidine blue, x480).
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Fig. 15 (Burns and Feeney). Top, Hypermature cataract, right eye. Note the wrinkled capsule and acellular amorphous appearance of the cortical fibers (paraffin, hematoxylin and eosin, x 160). Bottom, Hypermature cataract, left eye. Toluidine blue-positive streaks in the cortex may be nuclear remnants. Note the macrophages (open arrow) outside the capsule apparently transforming into fibroblastic cells (solid arrow) (plastic, toluidine blue, x 130).
of nuclear material, persistence of nuclei, cellular necrosis, edema, and cell rupture. Abnormal proliferation of epithelial cells in this strain is secondary to early changes. 9 In another strain of cataract-prone mice (Nakano, cross-bred with Charles River albino mice), the lens develops normally until the sixth postnatal day. Thereafter, swelling of the distal portion in the deep posterior suture area was observed along with abnormalities of denucleation. 7 Bio chemical studies of these lenses indicated a deficiency of sodium-potassium activat ed adenosine triphosphate activity. 10 In
adequacy of the cation p u m p was respon sible for the increased hydration of the lens cells and later cataract formation. Cataracts in deer mice more closely resemble human senile lens opacities than most of the 12 types of experimental cataracts described by Duke-Elder. 6 Also, cataracts in deer mice resemble senile cataracts more than they resemble con genital or developmental cataracts (for example, late onset, cortical changes, opacities at the equator extending into the anterior and posterior cortex, and lique faction). Perhaps these cataracts resemble most closely posterior subcapsular senile
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cataract in that the opacity is tonfined to the zone immediately beneath the capsule (unlike secondary cataracts wherein the newformed lens fibers from the equator gradually crowd the posterior opacity for ward so it lies within the cortex). 5 The lens disease appears to occur after a considerable period of normal develop ment of the lens. The cataract begins when equatorial epithelial cells, which are beginning to differentiate into the long lens "fibers" that stretch from the front to the back of the lens, begin to vacuolate. Subsequently or concurrently vacuoles also appear in the apical and basal poles of these ribbon-like cells. Changes in the posterior lens cortical fibers cause epithelial cells at the equator to migrate backward. However, changes in anterior lens cortical fibers do not cause epithelial cells to migrate forward. This phenomenon has been observed in human cataracts for many years. Possibly the epithelial cells migrate posteriorly from the lens bow because of a demand for metabolic support, for example, to provide ion pumping in an area of fluid leakage. The anterior portions of the fi bers are covered by the anterior epitheli um and are therefore less vulnerable. Bio chemical and morphologic analysis of differences in the two areas of the lens could be revealing in further study of cataract development. The mechanism by which epithelial cells migrate is under study in this laboratory. 11 This paper is a preliminary report of a new, complex, and fascinating animal model of one of the commonest and cost liest human diseases. It affords a high degree of predictability of onset of dis ease, since syndactyly occurs before cata ract disease in lens cells. Some early mor phologic abnormalities were observed by light microscopy. Electron microscopy and biochemical studies may reveal the
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critical anomaly in these lenses. With this model, we may study differences in anter ior and posterior lens substances that might account for migration of equatorial cells posteriorly but not anteriorly. SUMMARY
A new type of hereditary cataract was predicted in the deer mouse (Peromyscus maniculatus) by the presence of syndac tyly of the hind feet. Early morphologic changes were found in the equatorial cells that differentiated into new lens fi bers. Later swelling at the anterior and posterior poles of these cells produced lens opacities. Anterior and posterior subcapsular cataracts progressed to a hypermature shrunken lens. REFERENCES 1. Huestis, R. R.: Eye pigmentation in Peromys cus. Proc. Oregon Acad. Sci. 2:85, 1951. 2. Anderson, R., Huestis, R. R., and Motulsky, A. G.: Hereditary spherocytosis in the deer mouse. Its similarity to the human disease. Blood 15:491, 1960. 3. Hill, J. L.: Peromyscus. Effect of early pairing on reproduction. Science 186:1042, 1974. 4. Rugh, R.: The Mouse. Minneapolis, Burgess Publishing Co., 1968, p. 246. 5. Hogan, M. J., and Zimmerman, L. E.: Ophthal mic Pathology. An Atlas and Textbook. Philadel phia, W. B. Saunders, 1964, pp. 655-687. 6. Duke-Elder, S., and Jay, B.: Diseases of the Lens and Vitreous. Glaucoma and Hypotony. In Duke Elder, S. (ed.): System of Ophthalmology, vol. 11, pt. 2. London, Henry Kimpton, 1969, pp. 76-78. 7. Hamai, Y., Fukui, H. N., and Kuwabara, T.: Morphology of hereditary mouse cataract. Exp. Eye Res. 18:537, 1974. 8. Hamai, Y., and Kuwabara, T.: Early cytologic changes in Fraser cataract. An electron microscopic study. Invest. Ophthalmol. In Press. 9. Zwaan, J., and Williams, R. M.: Cataracts and abnormal proliferation of the lens epithelium in mice carrying the Cat rr gene. Exp. Eye Res. 8:161, 1969. 10. Iwata, S., and Kinoshita, J. H.: Mechanism of development of hereditary cataract in mice. Invest. Ophthalmol. 10:504, 1971. 11. Gipson, I., Burns, R. P., and Wolfe-Lande, J.: Keratopathy in tyrosine-fed rats. Presented at the Association for Research in Vision and Ophthalmol ogy Spring meeting, Sarasota, Florida, April 30, 1975.
AND L Y N E T T E F E E N E Y , P H . D .
Portland, Oregon
necessary. 3 This decreases the frequency of the autosomal-recessive trait. Cataractous development can be pre dicted in deer mice born with clear lenses, because syndactyly of the middle toes of the hind feet occurs in animals destined to develop cataracts, and can be identified at 13 to 14 days of age. Some times the third and fourth toes on the front feet are fused, but this is less pre dictable for cataracts than syndactyly of the hind feet. The coincidence of the two defects is probably due to either gene linkage or pleiotropic effects of a single gene. Animals without toe fusion do not appear to inherit cataracts and are consid ered normal in this study.
It is a pleasure to dedicate this work to Michael Hogan. Teacher, friend, and in vestigator, he has been a leader in the integration of structure and function in the eye. This is the first report of predictable hereditary cataracts in the Peromyscus maniculatus (peros-maimed; mus-mouse) or deer mouse, a rodent found throughout the United States.* The cataract resem bles lens opacities that occur after acute metabolic insults or those that develop slowly during the aging process. We feel that this progressive lens opacification may be a model for the study of senile cataract. We studied a colony of deer mice for one year. Their cataracts are inherited as an autosomal-recessive trait. At first, cata racts were visible at 3 years of age. (The maximum life span of deer mice is 8 years). By selective breeding, the fre quency of cataracts increased, and be came visible at 2 months to 1 year of age. Brother and sister breeding attempts were carried out, but inbreeding decreased the frequency of mating in litters, so periodic outbreeding into unaffected deer mice is
M A T E R I A L S AND M E T H O D S
These Peromyscus were first studied by R. R. Huestis, Ph.D., University of Oregon, Eugene, Ore gon. While examining the inheritance of iris color, he noted that some of the animals had cataracts.1 A further hereditary defect includes neonatal jaundice that resembles hereditary spherocytosis in man.2 We obtained a colony through Ruth Anderson, Ph.D., Division of Immunology, University of Oregon Health Sciences Center, Portland, Oregon. From the John E. Weeks Memorial Laboratory of Ophthalmology, University of Oregon Medical School, Portland, Oregon. This study was supported in part by grants EY00753 and EY00715, and Re search to Prevent Blindness, Inc. Reprint requests to Robert P. Burns, M.D., John E. Weeks Memorial Laboratory of Ophthalmology, University of Oregon Medical School, Portland OR 97201.
Animals were maintained in animal quarters for one year. Deer mice breed by 6 weeks of age, and usually have two to four in a litter. The female deer mouse can breed the first day after giving birth to a litter. Sibling mating was encouraged, as was back breeding to the parent. We examined the animals with a HaagStreit 900 slit lamp. The deer mouse lens was large and the eyes dilated well with cycloplegics. Animals were anesthetized with methoxyflurane for slit-lamp pho tography. Selected animals were killed with an overdose of anesthetic. Whole heads of animals younger than 10 days old were fixed in 10% neutral formalin. After the eyelids opened at about 14 days, eyes were enucleated and placed in either 10% formalin for paraffin embedding or a 2% paraformaldehyde-1% glutaraldehyde mixture for plastic embedding. Some lenses were dissected from the globe be fore fixation, and others were dissected after fixation and before embedding. Par-
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affin sections were stained with hematoxylin and eosin. Epoxy sections were stained with toluidine blue-borax stain. RESULTS
Biomicroscopy—The head and fused toes of a deer mouse with white lenses are shown in Figures 1 and 2. The biomicroscopic findings varied from clear lens with normal Y sutures, to a diffuse nonlocalized haziness in the lens, to anterior subcapsular and posterior subcapsular opacities (Fig. 3, left and center), to a complete mature white cataract (Fig. 3, right). Wrinkled hypermature cataracts with iritis and atrophy of the entire globe occurred in the final stages of opacification. Iris anomalies also occurred. We noted colobomas of the iris in some ani mals with cataracts. Irides occasionally appeared atrophic with a hypermature cataract. Histology—Biomicroscopically, clear lenses from presumably normal deer mice with normal toes were histologically sim ilar to house mice 4 (Figs. 4 and 5). The lens in a 6- to 10-day-old deer mouse was round and filled the ocular cavity. The ciliary body and iris were rudimentary and a tunica vasculosa lentis was present. The lens bow contained many nuclei that spread deep and toward the anterior pole.
Fig. 1 (Burns and Feeney). Adult deer mouse has bilateral cataracts.
Fig. 2 (Burns and Feeney). Fused third and fourth toes (arrows) of the hind feet of a deer mouse.
The lens capsule was thin and zonular fibers were not visible. In plasticembedded sections, light and dark cells were scattered throughout the bow region (Fig. 6). We do not know whether these are indications of early disease or if more subtle abnormalities are present. At 25 days of age, about ten days after the eyelids opened, the lens appeared similar to a normal adult lens. There were fewer nuclei in the bow and the tunica vasculosa lentis disappeared. The lens was more lenticular but still occupied most of the eye. There was little differ ence in the 25-day-old specimen and a 2.5-year-old specimen from a deer mouse that had no fused toes and was not expect ed to develop a cataract. Pathology—The earliest pathologic changes in deer mice with fused toes that should have developed cataracts were vacuolation in and near the nuclei just inside the lens bow at the equator (Figs. 7 and 8). These cells at the equator of the lens, that are differentiating from anterior epithelium into lens fibers, seem to be the morphologic site of the initial pathology (Fig. 9). The equatorial cells of the lens migrat ed posteriorly under the lens capsule in the animals that developed posterior sub capsular cataracts (Fig. 10). The basal
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Fig. 3 (Burns and Feeney). Left, Slit-lamp photograph of a young adult deer mouse showing a posterior subcapsular cataract. Slit beam passes through cornea (C), iris (I), anterior lens surface (L), and cataract on posterior lens. Center, Front view, slit-lamp photograph of central posterior subcapsular cataract with an uneven, whorled appearance. Pupil is widely dilated; L indicates lens. Right, Slit-lamp photograph of a mature cataract. ends of the superficial cortical cells (that is, the posterior subcapsular lens fibers) had striations and disruptions in
paraffin-embedded sections (Fig. 11, left). The same specimen, embedded in plastic, had a different morphology: the most su-
Fig. 4 (Burns and Feeney.) Coronal section through the head of a 6-day-old deer mouse showing normal histology. Eyelids are still fused; cornea (C), lens (L), and retina (R) (paraffin, hematoxylin and eosin, x32).
Fig. 5 (Burns and Feeney). Section through lens equator in a 6-day-old normal lens showing distri bution of nuclei at the bow (B) (paraffin, hematoxy lin and eosin, x 150).
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Fig. 7 (Burns and Feeney). Clear lens by slit lamp in infant deer mouse with fused toes. Note vacuolization of superficial fibers just anterior to the bow (arrow) (plastic, toluidine blue, x77).
perficial cells were swollen and irregular, whereas underlying cells appeared dense and shrunken (Fig. 11, right). Large epithelioid round cells collected in the posterior subcapsular region in plaques, similar to cells described as "bladder" or "Wedl" cells 5 in human cataracts (Fig. 12). The anterior and pos terior poles of the same lens showed a large posterior subcapsular cataract but a relatively normal anterior surface (Fig. 13). However, the nuclei of the epithelial cells in the anterior lens appeared some what pyknotic. The anterior cortex in some lenses showed degeneration of superficial lens Fig. 6 (Burns and Feeney). Montage of lens equa tor in a normal infant deer mouse. Note normal appearance of epithelium and superficial lens fibers; T indicates tunica vasculosa lentis (plastic, toluidine blue, x420).
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Fig. 8 (Burns and Feeney). Enlargement of a portion of Figure 7. Note vacuolization near nuclei at the lens bow (plastic, toluidine blue, xlOO). fibers with pooling of the cytoplasmic protein into globules, while the overlying epithelium appeared relatively unaffect ed (Fig. 14). Proliferation of anterior epi thelium did not occur. As anterior cortical
Fig. 9 (Burns and Feeney). Montage of equatorial region of adult hazy lens. Compare the abnormali ties in spacing of nuclei (thin arrows) and in density of newly formed lens fibers (thick arrows) with those of normal lens in Figure 6. (Dots are an artifact of uneven staining.) Enclosed area is enlarged in inset (x250). Inset, Note dense cytoplasm of several ab normal lens fibers (arrows) (plastic, toluidine blue, X420).
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Fig. 10 (Burns and Feeney). Adult with hazy lens by slit lamp. Nuclei lie in several clusters at abnor mally posterior subcapsular sites (arrows) (paraffin, hematoxylin and eosin, x38).
opacities developed, the rest of the lens was obscured, and slit-lamp assessment of other abnormalities in these eyes was impossible. After cataracts developed in the super ficial cortex, either anteriorly or posterior ly, the lens nuclei disappeared with de velopment of a total cataract (Fig. 15). Wrinkling of the capsule, causing a small er lens, presumably resulted from a loss of protein through the lens capsule (Fig. 15). Inflammation in either the anterior or posterior chambers of the eye occasional ly occurred, with attraction of macrophages (Fig. 15, bottom), that eventually transformed into fibrocytes. Iris atrophy and retinal detachment occasionally en-
Fig. 11 (Burns and Feeney). Left, Posterior sutun area of same lens as in Figure 10- (paraffin, hematox ylin and eosin, x250). Right, Posterior suture area o fellow lens embedded in plastic. Note irregularitie; of superficial cells and various densities of deepe cells (plastic, toluidine blue, x250).
Fig. 12 (Burns and Feeney). Posterior subcapsuk cataract. Note epithelioid cells (paraffin, hematoxy lin and eosin x42).
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Fig. 14 (Burns and Feeney). Anterior cortical cataract (paraffin, hematoxylin and eosin, x38).
sued, as observed in human hypermature cataract. DISCUSSION
Although there are many ways to pro duce experimental cataracts, "none of these has yet offered a definite clue to the intimate mechanism involved in the oc currence of the usual lenticular opacities in man." 6 Spontaneously developing cat aracts provide an opportunity to study the biochemical and morphologic sequence of events leading to opacification. Hereditary cataracts in the house mouse (Mas musculus) have been de scribed. 7 These cataracts are visible by the 25th postnatal day and may be detect ed histologically in prenatal lenses. Vari ous defects in the morphogenesis and maturation of the lens cells have been described in mice. In the Fraser cataract strain, abnormalities in cells of the invaginating lens vesicle have been reported. 8 Many later steps in lens cell differen tiation are also abnormal, such as irreg ularities in cellular elongation, leakage
Fig. 13 (Burns and Feeney). Top, Anterior surface of eye whose slit-lamp appearance is shown in Figure 3, left. Nuclei (arrow) are somewhat pyknotic and resemble those about to undergo dissolution in the lens bow as they are displaced deeper into lens cortex (plastic, toluidine blue, x240). Bottom, Pos terior subcapsular cataract. Irregularities produced by various depths of epithelioid cell plaques corre spond to various densities of the cataract shown in Figure 3, left and center (paraffin, plastic, toluidine blue, x480).
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Fig. 15 (Burns and Feeney). Top, Hypermature cataract, right eye. Note the wrinkled capsule and acellular amorphous appearance of the cortical fibers (paraffin, hematoxylin and eosin, x 160). Bottom, Hypermature cataract, left eye. Toluidine blue-positive streaks in the cortex may be nuclear remnants. Note the macrophages (open arrow) outside the capsule apparently transforming into fibroblastic cells (solid arrow) (plastic, toluidine blue, x 130).
of nuclear material, persistence of nuclei, cellular necrosis, edema, and cell rupture. Abnormal proliferation of epithelial cells in this strain is secondary to early changes. 9 In another strain of cataract-prone mice (Nakano, cross-bred with Charles River albino mice), the lens develops normally until the sixth postnatal day. Thereafter, swelling of the distal portion in the deep posterior suture area was observed along with abnormalities of denucleation. 7 Bio chemical studies of these lenses indicated a deficiency of sodium-potassium activat ed adenosine triphosphate activity. 10 In
adequacy of the cation p u m p was respon sible for the increased hydration of the lens cells and later cataract formation. Cataracts in deer mice more closely resemble human senile lens opacities than most of the 12 types of experimental cataracts described by Duke-Elder. 6 Also, cataracts in deer mice resemble senile cataracts more than they resemble con genital or developmental cataracts (for example, late onset, cortical changes, opacities at the equator extending into the anterior and posterior cortex, and lique faction). Perhaps these cataracts resemble most closely posterior subcapsular senile
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cataract in that the opacity is tonfined to the zone immediately beneath the capsule (unlike secondary cataracts wherein the newformed lens fibers from the equator gradually crowd the posterior opacity for ward so it lies within the cortex). 5 The lens disease appears to occur after a considerable period of normal develop ment of the lens. The cataract begins when equatorial epithelial cells, which are beginning to differentiate into the long lens "fibers" that stretch from the front to the back of the lens, begin to vacuolate. Subsequently or concurrently vacuoles also appear in the apical and basal poles of these ribbon-like cells. Changes in the posterior lens cortical fibers cause epithelial cells at the equator to migrate backward. However, changes in anterior lens cortical fibers do not cause epithelial cells to migrate forward. This phenomenon has been observed in human cataracts for many years. Possibly the epithelial cells migrate posteriorly from the lens bow because of a demand for metabolic support, for example, to provide ion pumping in an area of fluid leakage. The anterior portions of the fi bers are covered by the anterior epitheli um and are therefore less vulnerable. Bio chemical and morphologic analysis of differences in the two areas of the lens could be revealing in further study of cataract development. The mechanism by which epithelial cells migrate is under study in this laboratory. 11 This paper is a preliminary report of a new, complex, and fascinating animal model of one of the commonest and cost liest human diseases. It affords a high degree of predictability of onset of dis ease, since syndactyly occurs before cata ract disease in lens cells. Some early mor phologic abnormalities were observed by light microscopy. Electron microscopy and biochemical studies may reveal the
SEPTEMBER, 1975
critical anomaly in these lenses. With this model, we may study differences in anter ior and posterior lens substances that might account for migration of equatorial cells posteriorly but not anteriorly. SUMMARY
A new type of hereditary cataract was predicted in the deer mouse (Peromyscus maniculatus) by the presence of syndac tyly of the hind feet. Early morphologic changes were found in the equatorial cells that differentiated into new lens fi bers. Later swelling at the anterior and posterior poles of these cells produced lens opacities. Anterior and posterior subcapsular cataracts progressed to a hypermature shrunken lens. REFERENCES 1. Huestis, R. R.: Eye pigmentation in Peromys cus. Proc. Oregon Acad. Sci. 2:85, 1951. 2. Anderson, R., Huestis, R. R., and Motulsky, A. G.: Hereditary spherocytosis in the deer mouse. Its similarity to the human disease. Blood 15:491, 1960. 3. Hill, J. L.: Peromyscus. Effect of early pairing on reproduction. Science 186:1042, 1974. 4. Rugh, R.: The Mouse. Minneapolis, Burgess Publishing Co., 1968, p. 246. 5. Hogan, M. J., and Zimmerman, L. E.: Ophthal mic Pathology. An Atlas and Textbook. Philadel phia, W. B. Saunders, 1964, pp. 655-687. 6. Duke-Elder, S., and Jay, B.: Diseases of the Lens and Vitreous. Glaucoma and Hypotony. In Duke Elder, S. (ed.): System of Ophthalmology, vol. 11, pt. 2. London, Henry Kimpton, 1969, pp. 76-78. 7. Hamai, Y., Fukui, H. N., and Kuwabara, T.: Morphology of hereditary mouse cataract. Exp. Eye Res. 18:537, 1974. 8. Hamai, Y., and Kuwabara, T.: Early cytologic changes in Fraser cataract. An electron microscopic study. Invest. Ophthalmol. In Press. 9. Zwaan, J., and Williams, R. M.: Cataracts and abnormal proliferation of the lens epithelium in mice carrying the Cat rr gene. Exp. Eye Res. 8:161, 1969. 10. Iwata, S., and Kinoshita, J. H.: Mechanism of development of hereditary cataract in mice. Invest. Ophthalmol. 10:504, 1971. 11. Gipson, I., Burns, R. P., and Wolfe-Lande, J.: Keratopathy in tyrosine-fed rats. Presented at the Association for Research in Vision and Ophthalmol ogy Spring meeting, Sarasota, Florida, April 30, 1975.