Retinal degeneration in transgenic mice with photoreceptor-specific expression of a dominant-negative fibroblast growth factor receptor

Campochiaro, P.; Chang, Michelle; Ohsato, Masahiko; Sa, Vinores; Nie, Zhongzhen; Hjelmeland, Leonard M.; Mansukhani, A; Basilico, Claudio; Zack, D. J.

doi:10.1523/jneurosci.16-05-01679.1996

Cited by 77 publications

(61 citation statements)

References 36 publications

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“…We showed that this mutant receptor inhibited activation of wild-type EphA receptors both in vitro and in transgenic mice. This finding is consistent with several previous studies that kinase-null mutant receptors inhibit activation of wild-type receptors both in vitro and in transgenic animals (32)(33)(34)(35)(36). The truncated receptor may inhibit endogenous receptor function by several potential mechanisms.…”

Section: Expression Of a Truncated Epha Receptor Alters Hippocampal Axonsupporting

confidence: 93%

Mistargeting hippocampal axons by expression of a truncated Eph receptor

Yue

Chen

Gale

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Topographic mapping of axon terminals is a general principle of neural architecture that underlies the interconnections among many neural structures. The Eph family tyrosine kinase receptors and their ligands, the ephrins, have been implicated in the formation of topographic projection maps. We show that multiple Eph receptors and ligands are expressed in the hippocampus and its major subcortical projection target, the lateral septum, and that expression of a truncated Eph receptor in the mouse brain results in a pronounced alteration of the hippocamposeptal topographic map. Our observations provide strong support for a critical role of Eph family guidance factors in regulating ontogeny of hippocampal projections.I nformation encoding as topographic maps, which reflects the spatial organization of sensory surfaces and body effectors, is a fundamental mechanism of nervous system function (1, 2). Such topographic representation is critically dependent on precise ordering of axon projections, which maintains the spatial organization of neurons in synaptic connections with target neurons. It has been suggested that topographic axon connections allow transfer of spatial information in the sensory systems (3). In the eye, retinal axons form an inverted projection map in the tectum, with dorsal axons projecting to the ventral tectum, and ventral axons to the dorsal tectum. Similarly, retinal ganglion neurons in the temporal and nasal sides send axons to the anterior and posterior regions of the tectum, respectively (4). Comparable mechanisms may also operate in the limbic circuits, where learning, memory, and emotional responses are elaborated. For example, the hippocampus sends axons topographically to the lateral septum, with dorsomedial neurons projecting to the dorsomedial area of the target, and ventrolateral neurons projecting to the ventrolateral septal region (5, 6). Similarity in organizational principles between limbic circuits and sensory systems suggests that learning, memory, and emotions may be governed by the same spatial constraints as sensory information processing.Based on analyses of regenerating retinal axons, Roger Sperry (7) proposed that axons and target neurons carry specific cytochemical identification tags, and that each axon makes synaptic connections only with neurons carrying matching affinity tags. These tags may be distributed as gradients in the projecting and target fields to specify topographic maps. Recent expression and functional studies suggest that ephrins and their receptors serve as the postulated chemoaffinity guidance tags. The ephrins are a family of cell surface molecules that are ligands of the Eph family tyrosine kinase receptors (8). The Eph receptors, EphA3 in the chicken and EphA5͞A6 in the mouse retina, are expressed in a nasal (low) to temporal (high) gradient (3, 9, 10). Complementary to the receptor gradient, the ligands ephrin-A2 and -A5 constitute an anterior (low) to posterior (high) gradient in the optic tectum (9, 11-13). Disruption of the ligand gradient by re...

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Section: Expression Of a Truncated Epha Receptor Alters Hippocampal Axonsupporting

confidence: 93%

Mistargeting hippocampal axons by expression of a truncated Eph receptor

Yue

Chen

Gale

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…Meeson and R.A.L., unpublished), confirmation that growth factor deprivation-induced apoptosis is an important component of capillary regression awaits further experimentation. This mechanism is consistent with the emerging view that all cells are dependent on growth factors for their survival in vivo (Angeletti et al, 1971;Raff, 1992;Chow et al, 1995;Campochiaro et al, 1996) and in particular with the recent observation that endothelial cell growth factors have survival stimulating activity (Alon et al, 1995).…”

Section: Is Flow Stasis Required For Programmed Capillary Regression?supporting

confidence: 88%

“…The most likely explanation for this observation is that lens fiber cells are dependent upon FGF for their survival as well as for their differentiation (Chow et al, 1995;Robinson et al, 1995a). This would certainly be consistent with an expanding literature documenting the survival stimulating activity of a variety of growth factors in vitro and in vivo (Angeletti et al, 1971;Raff, 1992;Campochiaro et al, 1996).…”

Section: Growth Factor Signal Deprivation Induces Apoptosis Of Lens Fsupporting

confidence: 86%

Apoptosis in mammalian eye development: lens morphogenesis, vascular regression and immune privilege

Lang

1997

Cell Death Differ

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Formation of the mammalian eye requires a complex series of tissue interactions that result in an organ of exquisite sensory capability. The early steps in eye development involve extensive cell death associated with morphogenesis. Later, suppression of programmed cell death is essential for tissue differentiation and in the adult, the immune privileged status of the eye is maintained in part through factors that induce inflammatory cell apoptosis. Experimental evidence suggests that suppression of apoptosis in cells of the lens lineage by fibroblast growth factors is one component of their action during lens morphogenesis. Fibroblast growth factors are also required for normal lens fiber-cell differentiation. This includes a degenerative step for organelles that is presumably an adaptation for the clearance of light scattering elements from the optic axis. The process of organelle degeneration may be related to apoptosis in a few of its features. Activelyinduced apoptosis becomes important for eye development as the temporary ocular vasculatures regress. This too, is presumably an adaptation for the disposal of cells that would disturb the passage of light to the retina. Ocular macrophages appear to be essential for the induction of apoptosis in the endothelial cells comprising the ocular vasculatures. In the adult, inflammatory cells entering the eye are exposed to the pro-apoptotic agents transforming growth factor-b2 and Fas ligand. The expression of these molecules in the eye, and their action in killing inflammatory cells, has evolved as a means of preventing inflammation and subsequent loss of vision. Thus, the eye offers a unique and versatile system for studying the role of programmed cell death in lens development, vascular regression and immune privilege.

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“…It was shown that inhibition of the FGFR1-mediated pathway in Xenopus embryos resulted in a 50% loss of photoreceptor and amacrine cells, with a concomitant increase of Müller cells (McFarlane et al, 1998). The role of FGF signaling through receptors FGFR1 and FGFR2 in the survival of murine photoreceptor cells has also been investigated (Campochiaro et al, 1996). These authors demonstrated that inhibition of FGF signaling using ∆FGFR1 and ∆FGFR2 resulted in a progressive death of photoreceptor cells.…”

Section: Introductionmentioning

confidence: 99%

Targeted expression of the dominant-negative FGFR4a in the eye usingXrx1Aregulatory sequences interferes with normal retinal development

et al. 2003

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Molecular analysis of vertebrate eye development has been hampered by the availability of sequences that can selectively direct gene expression in the developing eye. We report the characterization of the regulatory sequences of the Xenopus laevis Rx1A gene that can direct gene expression in the retinal progenitor cells. We have used these sequences to investigate the role of Fibroblast Growth Factor (FGF) signaling in the development of retinal cell types. FGFs are signaling molecules that are crucial for correct patterning of the embryo and that play important roles in the development of several embryonic tissues. FGFs and their receptors are expressed in the developing retina, and FGF receptor-mediated signaling has been implicated to have a role in the specification and survival of retinal cell types. We investigated the role of FGF signaling mediated by FGF receptor 4a in the development of retinal cell types in Xenopus laevis. For this purpose, we have made transgenic Xenopus tadpoles in which the dominant-negative FGFR4a(ΔFGFR4a) coding region was linked to the newly characterized regulatory sequences of the Xrx1A gene. We found that the expression ofΔFGFR4a in retinal progenitor cells results in abnormal retinal development. The retinas of transgenic animals expressing ΔFGFR4a show disorganized cell layering and specifically lack photoreceptor cells. These experiments show that FGFR4a-mediated FGF signaling is necessary for the correct specification of retinal cell types. Furthermore, they demonstrate that constructs using Xrx1A regulatory sequences are excellent tools with which to study the developmental processes involved in retinal formation.

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Retinal degeneration in transgenic mice with photoreceptor-specific expression of a dominant-negative fibroblast growth factor receptor

Cited by 77 publications

References 36 publications

Mistargeting hippocampal axons by expression of a truncated Eph receptor

Mistargeting hippocampal axons by expression of a truncated Eph receptor

Apoptosis in mammalian eye development: lens morphogenesis, vascular regression and immune privilege

Targeted expression of the dominant-negative FGFR4a in the eye usingXrx1Aregulatory sequences interferes with normal retinal development

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