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Zhou S.,Stem Cell and Developmental Biology Laboratory | Flamier A.,Stem Cell and Developmental Biology Laboratory | Abdouh M.,Stem Cell and Developmental Biology Laboratory | Tetreault N.,Stem Cell and Developmental Biology Laboratory | And 4 more authors.
Development (Cambridge) | Year: 2015

Cone photoreceptors are required for color discrimination and highresolution central vision and are lost in macular degenerations, cone and cone/rod dystrophies. Cone transplantation could represent a therapeutic solution. However, an abundant source of human cones remains difficult to obtain. Work performed in model organisms suggests that anterior neural cell fate is induced ‘by default’ if BMP, TGFβ and Wnt activities are blocked, and that photoreceptor genesis operates through an S-cone default pathway. We report here that Coco (Dand5), a member of the Cerberus gene family, is expressed in the developing and adult mouse retina. Upon exposure to recombinant COCO, human embryonic stem cells (hESCs) differentiated into S-cone photoreceptors, developed an inner segment-like protrusion, and could degrade cGMP when exposed to light. Addition of thyroid hormone resulted in a transition from a unique S-cone population toward a mixed M/S-cone population. When cultured at confluence for a prolonged period of time, COCOexposed hESCs spontaneously developed into a cellular sheet composed of polarized cone photoreceptors. COCO showed dosedependent and synergistic activity with IGF1 at blocking BMP/TGFβ/ Wnt signaling, while its cone-inducing activity was blocked in a dosedependent manner by exposure to BMP, TGFβ or Wnt-related proteins. Our work thus provides a unique platform to produce human cones for developmental, biochemical and therapeutic studies and supports the hypothesis that photoreceptor differentiation operates through an S-cone default pathway during human retinal development. © 2015. Published by The Company of Biologists Ltd. Source


Barabino A.,Stem Cell and Developmental Biology Laboratory | Plamondon V.,Stem Cell and Developmental Biology Laboratory | Abdouh M.,Stem Cell and Developmental Biology Laboratory | Chatoo W.,Stem Cell and Developmental Biology Laboratory | And 8 more authors.
Development (Cambridge) | Year: 2016

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. © 2016. Published by The Company of Biologists Ltd. Source


Abdouh M.,University of Montreal | Abdouh M.,Stem Cell and Developmental Biology Laboratory | Hanna R.,University of Montreal | Hanna R.,Stem Cell and Developmental Biology Laboratory | And 6 more authors.
Journal of Biological Chemistry | Year: 2016

The polycomb repressive complex 1 (PRC1), containing the core BMI1 and RING1A/B proteins, mono-ubiquitinylates histone H2A (H2Aub) and is associated with silenced developmental genes at facultative heterochromatin. It is, however, assumed that the PRC1 is excluded from constitutive heterochromatin in somatic cells based on work performed on mouse embryonic stem cells and oocytes. We show here that BMI1 is required for constitutive heterochromatin formation and silencing inhuman and mouse somatic cells. BMI1 was highly enriched at intergenic and pericentric heterochromatin, co-immunoprecipitated with the architectural heterochromatin proteins HP1, DEK1, and ATRx, and was required for their localization. In contrast, BRCA1 localization was BMI1-independent and partially redundant with that of BMI1 for H2Aub deposition, constitutive heterochromatin formation, and silencing. These observations suggest a dynamic and developmentally regulated model of PRC1 occupancy at constitutive heterochromatin, and where BMI1 function in somatic cells is to stabilize the repetitive genome. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Source

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