The vertebrate lens provides an excellent model to study the mechanisms that regulate terminal differentiation. Although fibroblast growth factors (FGFs) are thought to be important for lens cell differentiation, it is unclear which FGF receptors mediate these processes during different stages of lens development. Deletion of three FGF receptors (Fgfr1-3) early in lens development demonstrated that expression of only a single allele of Fgfr2 or Fgfr3 was sufficient for grossly normal lens development, while mice possessing only a single Fgfr1 allele developed cataracts and microphthalmia. Profound defects were observed in lenses lacking all three Fgfrs. These included lack of fiber cell elongation, abnormal proliferation in prospective lens fiber cells, reduced expression of the cell cycle inhibitors p27(kip1) and p57(kip2), increased apoptosis and aberrant or reduced expression of Prox1, Pax6, c-Maf, E-cadherin and alpha-, beta- and gamma-crystallins. Therefore, while signaling by FGF receptors is essential for lens fiber differentiation, different FGF receptors function redundantly.
During normal differentiation, lens fiber cells lose their nuclei, mitochondria, and other membrane-bound organelles. In the present study, a slice preparation of the embryonic chicken lens was used with laser scanning confocal microscopy to study the spatial and temporal patterns of organelle breakdown during embryonic development. At all stages examined, mitochondria in lens epithelial cells were present in perinuclear clusters. In contrast, early in development, lens fiber cells contained extremely elongated mitochondria (>lo0 pm) that were distributed throughout the cytoplasm and oriented along the long axis of the cells. By the 8th day of embryonic development (E8), the mitochondria in the central fiber cells began to fragment. At the same time, the nuclei in these cells became smaller and more spherical. By E 10, mitochondria1 staining in the central fibers became punctate. Electron microscopy of this region revealed swollen mitochondria with disrupted cristae. By E12, cells in the central region of the lens lacked mitochondria and nuclei. The loss of nuclei and mitochondria from a given cell was coincident and abrupt (2-4 hr), occurring in a previously unsuspected domain situated about 300 pm from the anterior surface of the lens. A cytoskeletal component, actin, persisted in the central cells indicating that organelle degradation represents a selective process and not simply the global degradation of supramolecular structures. Throughout embryonic development, the organelle-free region grew at approximately the same rate as the lens and, by the time of hatching, had expanded to match the diameter of the pupil. The present results suggest that the embryonic lens will be a useful model system with which to study mechanisms of organelle degradation. o 1992 WiIey-Liss, Inc.
Purpose: Cataracts are often considered to be an unavoidable consequence of aging. Oxidative damage is a major cause or consequence of cortical and nuclear cataracts, the most common types of age-related cataracts. Methods: In this review, we consider the different risk factors, natural history and etiology of each of the 3 major types of age-related cataract, as well as the potential sources of oxidative injury to the lens and the mechanisms that protect against these insults. The evidence linking different oxidative stresses to the different types of cataracts is critically evaluated. Results: We conclude from this analysis that the evidence for a causal role of oxidation is strong for nuclear, but substantially lower for cortical and posterior subcapsular cataracts. The preponderance of evidence suggests that exposure to increased levels of molecular oxygen accelerates the age-related opacification of the lens nucleus, leading to nuclear cataract. Factors in the eye that maintain low oxygen partial pressure around the lens are, therefore, important in protecting the lens from nuclear cataract. Conclusions: Maintaining or restoring the low oxygen partial pressure around that lens should decrease or prevent nuclear cataracts.
Oxygen metabolism by the lens and cornea establishes oxygen gradients in the anterior segment. Vitrectomy and cataract surgery increase pO(2) in the anterior chamber angle, potentially damaging trabecular meshwork cells. We propose that oxygen levels in the anterior chamber angle are strongly influenced by oxygen derived from the ciliary body circulation.
Limb buds of chicken embryos contain within the peripheral mesoderm an avascular zone that is rich in hyaluronic acid. Epithelial tissues that synthesize large amounts of hyaluronic acid relative to other glycosaminoglycans caused avascularity when implanted into normally vascular wing mesoderm. Epithelia that synthesize little hyaluronic acid did not cause avascularity. Elvax implants containing hyaluronic acid caused the formation of avascular zones, whereas similar implants containing other glycosaminoglycans did not give rise to avascular zones. Hyaluronic acid may thus play a role in determining the location of blood vessels in the embryo.
Although placodes are ubiquitous precursors of tissue invagination, the mechanism of placode formation has not been established and the requirement of placode formation for subsequent invagination has not been tested. Earlier measurements in chicken embryos supported the view that lens placode formation occurs because the extracellular matrix (ECM) between the optic vesicle and the surface ectoderm prevents the prospective lens cells from spreading. Continued cell proliferation within this restricted area was proposed to cause cell crowding, leading to cell elongation (placode formation). This view suggested that continued cell proliferation and adhesion to the ECM between the optic vesicle and the surface ectoderm was sufficient to explain lens placode formation. To test the predictions of this “restricted expansion hypothesis,” we first confirmed that the cellular events that accompany lens placode formation in chicken embryos also occur in mouse embryos. We then showed that the failure of lens placode formation when the transcription factor, Pax6 was conditionally deleted in the surface ectoderm was associated with greatly diminished accumulation of ECM between the optic vesicle and ectoderm and reduced levels of transcripts encoding components of the ECM. In accord with the “restricted expansion hypothesis,” the Pax6-deleted ectoderm expanded, rather than being constrained to a constant area. As a further test, we disrupted the ECM by deleting Fn1, which is required for matrix assembly and cell-matrix adhesion. As in Pax6CKO embryos, the Fn1CKO lens ectoderm expanded, rather than being constrained to a fixed area and the lens placode did not form. Ectoderm cells in Fn1CKO embryos expressed markers of lens induction and reorganized their cytoskeleton as in wild type ectoderm, but did not invaginate, suggesting that placode formation establishes the minimal mechanical requirements for invagination.
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