Barabino Andrea, Plamondon Vicky, Abdouh Mohamed, Chatoo Wassim, Flamier Anthony, Hanna Roy, Zhou Shufeng, Motoyama Noboru, Hébert Marc, Lavoie Joëlle, Bernier Gilbert
Stem Cell and Developmental Biology Laboratory, Hôpital Maisonneuve-Rosemont, 5415 Boul. l'Assomption, Montréal, Canada H1T 2M4.
Department of Cognitive Brain Science, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan.
Development. 2016 May 1;143(9):1571-84. doi: 10.1242/dev.125351. Epub 2016 Mar 10.
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.
视网膜发育通过六种神经元细胞和一种神经胶质细胞类型的顺序性但重叠性生成而发生。其中，视杆和视锥光感受器代表光检测和光转导的功能单元，并且在视网膜退行性疾病中经常受到影响。在小鼠发育过程中，多梳蛋白家族蛋白Bmi1在未成熟的视网膜祖细胞以及包括视锥细胞在内的分化视网膜神经元中表达。我们在此表明，Bmi1是预防视锥光感受器和双极神经元出生后退化所必需的，并且Chk2或p53的失活可以改善但不能克服Bmi1基因敲除小鼠中的视锥细胞退化。Bmi1基因敲除小鼠的视网膜表型还具有异染色质丢失、串联重复序列激活、氧化应激和Rip3相关坏死性凋亡的特征。在人类视网膜中，BMI1在异染色质位点的视锥细胞中优先表达。人类胚胎干细胞中BMI1的失活与视网膜诱导相容，但损害了视锥细胞的终末分化。尽管存在这种发育停滞，BMI1缺陷的视锥细胞重现了在Bmi1基因敲除光感受器中观察到的几种异常，如异染色质丢失、串联重复序列激活和p53的诱导，揭示了小鼠和人类之间部分保守的生物学功能。
