Pias3-dependent SUMOylation directs rod photoreceptor development.
Specification of retinal rod photoreceptors is determined by several different transcription factors that activate expression of rod-specific genes and repress expression of cone photoreceptor-specific genes. The mechanism by which this dual regulation occurs is unclear. We have found that Pias3, a transcriptional coregulator and E3 SUMO ligase that is selectively expressed in developing photoreceptors, promotes the differentiation of rod photoreceptors while preventing rods from adopting cone photoreceptor-like characteristics. Pias3 binds the photoreceptor-specific transcription factors Crx and Nr2e3 and is specifically targeted to the promoters of photoreceptor-specific genes. Pias3 SUMOylates Nr2e3, converting it into a potent repressor of cone-specific gene expression. Rod- and cone-specific promoters are bound by hyperSUMOylated proteins in rod photoreceptors, and blocking SUMOylation in photoreceptors results in cells with morphological and molecular features of cones and an absence of rod-specific markers. Our data thus identify Pias3-mediated SUMOylation of photoreceptor-specific transcription factors as a key mechanism of rod specification.
Onishi
Akishi
A
Department of Neuroscience, Johns Hopkins University School of Medicine, BRB 329, 733 North Broadway Avenue, Baltimore, MD 21287, USA.
Peng
Guang-Hua
GH
Hsu
Chengda
C
Alexis
Uel
U
Chen
Shiming
S
Blackshaw
Seth
S
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis / Q000502:physiology*; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology
D018398:Homeodomain Proteins; C485736:Nr2e3 protein, mouse; D057093:Orphan Nuclear Receptors; C109279:Pias3 protein, mouse; D050828:Protein Inhibitors of Activated STAT; D018160:Receptors, Cytoplasmic and Nuclear; D025842:SUMO-1 Protein; D015534:Trans-Activators; C109288:cone rod homeobox protein