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Development. 2018 Jul 9. pii: dev.163691. doi: 10.1242/dev.163691. [Epub ahead of print]

Pax6 regulation of Sox9 in the retinal pigmented epithelium controls its timely differentiation and choroid vasculature development.

Author information

1
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Sagol School of Neurosciences, Tel Aviv University, Tel Aviv 69978, Israel.
2
Department of Particle Physics, Raymond and Beverly Sackler School of Physics and Astronomy, Tel-Aviv University, Tel Aviv 69978, Israel.
3
Department of Neurobiology, Biochemistry and Biophysics school, George S. Wise Faculty of Life Sciences, Sagol School for Neuroscience, Tel-Aviv University, Tel Aviv 69978, Israel.
4
The Hadassah Human Embryonic Stem Cell Research Center, The Goldyne Savad Institute of Gene Therapy and The Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
5
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
6
University of Pennsylvania Perelman School of Medicine12-126 Smilow Center for Translational Research, 3400 Civic Center Blvd, Philadelphia, PA 19104-6145, USA.
7
Sagol School for Neuroscience, Tel-Aviv University, Tel Aviv 69978, Israel.
8
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Sagol School of Neurosciences, Tel Aviv University, Tel Aviv 69978, Israel ruthash@post.tau.ac.il ranel@tauex.tau.ac.il.

Abstract

The synchronized differentiation of neuronal and vascular tissues is crucial for normal organ development and function, although there is limited information about the mechanisms regulating the coordinated development of these tissues. The choroid vasculature of the eye serves as the main blood supply to the metabolically active photoreceptors, and develops together with the retinal pigmented epithelium (RPE). Here, we describe a novel regulatory relationship between the RPE transcription factors, Pax6 and Sox9, which control the timing of RPE differentiation, and the adjacent choroid maturation. We used a novel machine learning algorithm tool to analyze high resolution imaging of the choroid in Pax6 and Sox9 conditional mutant mice. Additional unbiased transcriptomic analyses in mutant mice and RPE cells generated from human embryonic stem cells, as well as chromatin immunoprecipitation and high throughput analyses, revealed secreted factors that are regulated by Pax6 and Sox9. These factors may be involved in choroid development and in the pathogenesis of the common blinding disease, age-related macular degeneration (AMD).

KEYWORDS:

AMD; Choroid vasculature; Pax6; RPE; Sox9

PMID:
29986868
DOI:
10.1242/dev.163691

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