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Cell Death Dis. 2018 Mar 6;9(3):370. doi: 10.1038/s41419-018-0411-6.

Rb is required for retinal angiogenesis and lamination.

Zhou Y1,2, Wei R1,2, Zhang L3,4, Chen Y3,4, Lu S3,4, Liang C1, Wang Y1,2, Xiao L1, Zhang J2, Bremner R5,6, Chen D7,8,9,10.

Author information

1
Research Laboratory of Ophthalmology and Vision Sciences, Torsten-Wiesel Research Institute of World Eye Organization, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
2
Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.
3
Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
4
Departments of Ophthalmology and Visual Science, and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
5
Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada. bremner@lunenfeld.ca.
6
Departments of Ophthalmology and Visual Science, and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. bremner@lunenfeld.ca.
7
Research Laboratory of Ophthalmology and Vision Sciences, Torsten-Wiesel Research Institute of World Eye Organization, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. danianchen2006@qq.com.
8
Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China. danianchen2006@qq.com.
9
Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada. danianchen2006@qq.com.
10
Departments of Ophthalmology and Visual Science, and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. danianchen2006@qq.com.

Abstract

Retinoblastoma tumor suppressor (Rb) promotes cell cycle exit, survival, differentiation, and tumor suppression in the retina. Here, we show it is also essential for vascularization and lamination. Despite minimal effects on Hif1a target expression, intraretinal vascular plexi did not form in the Rb -/- murine retina. Deleting adenovirus E2 promoter binding factor 3 (E2f3), which rescues starburst amacrine cell differentiation, or E2f2, had no effect, but deleting E2f1, which promotes neuronal cell cycle exit and survival, restored retinal vasculature. We specifically linked cell loss to the defect because removing Bax rescued rod and bipolar neurons and the vasculature, but not cell cycle exit. Despite rescuing Rb -/- neurons, Bax deletion exacerbated a delay in outer retina lamination, and exposed a requirement for Rb in inner retina lamination. The latter resembled Sem5 or FAT atypical cadherin 3 (Fat3) mutants, but expression of Sem5/Fat3 pathway components, or that of Neogenin, which perturbs migration in the Rb -/- cortex, was unchanged. Instead, lamination defects correlated with ectopic division, and were E2f1-dependent, implicating the cell cycle machinery. These in vivo studies expose new developmental roles for Rb, pinpoint aberrant E2f1 and Bax activity in neuronal death and vascular loss, and further implicate E2f1 in defective lamination. Links between Rb, angiogenesis and lamination have implications for the treatment of neovascularization, neurodegeneration and cancer.

PMID:
29511172
PMCID:
PMC5840357
DOI:
10.1038/s41419-018-0411-6
[Indexed for MEDLINE]
Free PMC Article

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