期刊
DEVELOPMENT
卷 143, 期 9, 页码 1571-1584出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.125351
关键词
Polycomb; Bmi1; Retina; Retinal development; Bipolar neuron; Cone; Photoreceptor; Degeneration; Mouse; Human; Embryonic stem cell
资金
- Natural Science and Engineering Research Council of Canada (NSERC)
- Antoine-Turmel Foundation for Macular Degeneration Research
- Foundation Fighting Blindness Canada
- NSERC
- Montreal University
- Reseau Vision du Quebec
Retinal development occurs through the sequential but overlapping generation of six types of neuronal cells and one glial cell type. Of these, rod and cone photoreceptors represent the functional unit of light detection and phototransduction and are frequently affected in retinal degenerative diseases. During mouse development, the Polycomb group protein Bmi1 is expressed in immature retinal progenitors and differentiated retinal neurons, including cones. We show here that Bmi1 is required to prevent post natal degeneration of cone photoreceptors and bipolar neurons and that inactivation of Chk2 or p53 could improve but not overcome cone degeneration in Bmi1(-/-) mice. The retinal phenotype of Bmi1(-/-) mice was also characterized by loss of heterochromatin, activation of tandem repeats, oxidative stress and Rip3-associated necroptosis. In the human retina, BMI1 was preferentially expressed in cones at heterochromatic foci. BMI1 inactivation in human embryonic stem cells was compatible with retinal induction but impaired cone terminal differentiation. Despite this developmental arrest, BMI1-deficient cones recapitulated several anomalies observed in Bmi1(-/-) photoreceptors, such as loss of heterochromatin, activation of tandem repeats and induction of p53, revealing partly conserved biological functions between mouse and man.
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