Retinal degeneration in the rd mouse in the absence of c-fos.

PURPOSE Apoptosis is the final common death pathway of photoreceptors in light-induced retinal degeneration and in several animal models for retinal dystrophy. To date, little is known about gene regulation of apoptosis in the retina. The expression of the immediate early gene c-fos is upregulated concomitant with apoptosis in light-induced photoreceptor degeneration and in the rd mouse, an animal model for inherited retinal degeneration. In a recent study it was shown that c-Fos is essential for light-induced apoptosis of photoreceptors in vivo. To determine whether c-Fos is also involved in the apoptotic pathway of inherited retinal degeneration, rd/rd, c-fos -/- double-mutant mice have been generated. METHODS Double-mutant mice (rd/rd, c-fos -/-) were crossbred from c-fos+/- mice and rd/rd mice. Their genotype was determined by polymerase chain reaction analysis of genomic DNA. Wild-type control mice and homozygous rd mice were killed at 2-day intervals from postnatal day (P)9 through P21. Double-mutant mice were killed at postnatal days P9, P11, P13, P15, and P21. To determine levels of apoptosis in the retina, eyes were enucleated and processed for light microscopy and in situ nick-end labeling. Total retinal DNA was extracted from isolated retinas for DNA fragmentation analysis. RESULTS Morphologic, histochemical, and biochemical analyses showed that the time course of apoptosis and the outcome of photoreceptor degeneration in rd/rd, c-fos-/- double-mutant mice was indistinguishable from that in rd mice carrying functional c-fos. CONCLUSIONS These data suggest that in contrast to its role in light-induced photoreceptor degeneration, c-Fos is not essential for apoptosis in the rd mouse.

[1]  R. Sidman,et al.  C57BL-6J mice with inherited retinal degeneration. , 1974, Archives of ophthalmology.

[2]  A. Bird,et al.  Retinal photoreceptor dystrophies LI. Edward Jackson Memorial Lecture. , 1995, American journal of ophthalmology.

[3]  B. Spiegelman,et al.  Pleiotropic effects of a null mutation in the c-fos proto-oncogene , 1992, Cell.

[4]  A. Milam,et al.  Apoptosis in Retinitis Pigmentosa , 1995 .

[5]  J. Barrett,et al.  Induction of apoptosis by c-Fos protein , 1996, Molecular and cellular biology.

[6]  W. Baehr,et al.  Identification of a nonsense mutation in the rod photoreceptor cGMP phosphodiesterase beta-subunit gene of the rd mouse. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Tiansen Li,et al.  Retinal degeneration in the rd mouse is caused by a defect in the β subunit of rod cGMP-phosphodiesterase , 1990, Nature.

[8]  Tsonwin Hai,et al.  Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[9]  I. Nir,et al.  Diurnal expression of c-fos in the mouse retina. , 1993, Brain research. Molecular brain research.

[10]  M. Cotten,et al.  Fos is an essential component of the mammalian UV response. , 1995, The EMBO journal.

[11]  Richard J Smeyne,et al.  Continuous c-fos expression precedes programmed cell death in vivo , 1993, Nature.

[12]  T. Li,et al.  Overexpression of Bcl-2 or Bcl-XL transgenes and photoreceptor degeneration. , 1996, Investigative ophthalmology & visual science.

[13]  S. Estus,et al.  Altered gene expression in neurons during programmed cell death: identification of c-jun as necessary for neuronal apoptosis , 1994, The Journal of cell biology.

[14]  J. Blanks,et al.  Aberrant expression of c-Fos accompanies photoreceptor cell death in the rd mouse. , 1997, Journal of neurobiology.

[15]  J. Nathans,et al.  Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[16]  J. Flannery,et al.  bcl-2 overexpression reduces apoptotic photoreceptor cell death in three different retinal degenerations. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Eithne Costello,et al.  Protein kinase A and AP-1 (c-Fos/JunD) are induced during apoptosis of mouse mammary epithelial cells. , 1994, Oncogene.

[18]  D. Liebermann,et al.  Proto-oncogenes of the fos/jun family of transcription factors are positive regulators of myeloid differentiation , 1993, Molecular and cellular biology.

[19]  C. Remé,et al.  The absence of c-fos prevents light-induced apoptotic cell death of photoreceptors in retinal degeneration in vivo , 1997, Nature Medicine.

[20]  M. Yaniv,et al.  Both Jun and Fos contribute to transcription activation by the heterodimer. , 1990, Oncogene.

[21]  M. Dragunow,et al.  Induction of immediate-early genes and the control of neurotransmitter-regulated gene expression within the nervous system. , 1995, Pharmacological reviews.

[22]  B. Franza,et al.  Fos and jun: The AP-1 connection , 1988, Cell.

[23]  C. Craft,et al.  Linkage of photoreceptor degeneration by apoptosis with inherited defect in phototransduction. , 1994, Investigative ophthalmology & visual science.

[24]  T. Curran,et al.  Kainic acid-induced neuronal death is associated with DNA damage and a unique immediate-early gene response in c-fos-lacZ transgenic rats , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[25]  John G. Flannery,et al.  The rd mouse story: Seventy years of research on an animal model of inherited retinal degeneration , 1994, Progress in Retinal and Eye Research.

[26]  D. Farber,et al.  Cyclic Guanosine Monophosphate: Elevation in Degenerating Photoreceptor Cells of the C3H Mouse Retina , 1974, Science.

[27]  S. Korsmeyer,et al.  Suppression of developmental retinal cell death but not of photoreceptor degeneration in Bax-deficient mice. , 1998, Investigative ophthalmology & visual science.

[28]  A. Di Polo,et al.  Transcriptional activation of the human rod cGMP-phosphodiesterase beta-subunit gene is mediated by an upstream AP-1 element. , 1997, Nucleic acids research.

[29]  T. Curran,et al.  Immediate-early genes: ten years on , 1995, Trends in Neurosciences.

[30]  W. Frankel,et al.  Localization of a retroviral element within the rd gene coding for the beta subunit of cGMP phosphodiesterase. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[31]  F. Mollinedo,et al.  C-Fos is not essential for apoptosis. , 1996, Biochemical and biophysical research communications.

[32]  J. Sonnenberg,et al.  Dynamic alterations occur in the levels and composition of transcription factor AP-1 complexes after seizure , 1989, Neuron.

[33]  Bernd Kaina,et al.  c-Fos is involved in the cellular defence against the genotoxic effect of UV radiation. , 1995, Carcinogenesis.

[34]  C. Remé,et al.  Light-induced apoptosis: differential timing in the retina and pigment epithelium. , 1997, Experimental eye research.

[35]  S. Ben‐Sasson,et al.  Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation , 1992, The Journal of cell biology.

[36]  M. Karin,et al.  The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. , 1991, Biochimica et biophysica acta.

[37]  R. Bravo,et al.  c-JUN, JUN B, and JUN D differ in their binding affinities to AP-1 and CRE consensus sequences: effect of FOS proteins. , 1991, Oncogene.

[38]  Y. Hao,et al.  Apoptosis: Final common pathway of photoreceptor death in rd, rds, and mutant mice , 1993, Neuron.

[39]  A. Mantovani,et al.  Expression and involvement of c-fos and c-jun protooncogenes in programmed cell death induced by growth factor deprivation in lymphoid cell lines. , 1992, The Journal of biological chemistry.

[40]  C. Grimm,et al.  Light-induced cell death of retinal photoreceptors in the absence of p53. , 1998, Investigative ophthalmology & visual science.