Abstract
BackgroundThe highly ordered vertebrate retina is composed of seven cell types derived from a common pool of retinal progenitor cells (RPCs), and is a good model for the studies of cell differentiation and interaction during neural development. Notch signaling plays a pivotal role in retinogenesis in mammals, but the full scope of the functions of Notch pathway, and the underlying molecular mechanisms, remain unclear.ResultsIn this study, we conditionally knocked out RBP-J, the critical transcription factor downstream to all four Notch receptors, in RPCs of mouse retina at different developmental stages. Disruption of RBP-J at early retinogenesis resulted in accelerated RPCs differentiation, but only photoreceptors and ganglion cells were overrepresented, with other neuronal populations diminished. Similarly, deletion of RBP-J at early postnatal days also led to overproduction of photoreceptors, suggesting that RBP-J governed RPCs specification and differentiation through retinogenesis. In all the RBP-J deletion models, the retinal laminar structures were distorted by the formation of numerous rosette-like structures, reminiscent of β-catenin deficient retina. Indeed, we found that these rosettes aligned with gaps in β-catenin expression at the apical surface of the retina. By in vivo electroporation-mediated transfection, we demonstrated that lamination defects in RBP-J deficient retinae were rescued by overexpressing β-catenin.ConclusionsOur data indicate that RBP-J-mediated canonical Notch signaling governs retinal cell specification and differentiation, and maintains retinal lamination through the expression of β-catenin.
Highlights
The highly ordered vertebrate retina is composed of seven cell types derived from a common pool of retinal progenitor cells (RPCs), and is a good model for the studies of cell differentiation and interaction during neural development
Because recombination signal-binding protein Jκ (RBP-J) binds to Notch intracellular domain (NICD) of all four mammalian Notch receptors, it serves as the key integrator of canonical Notch signaling [5,6]
Our results show that RBP-J-mediated canonical Notch signaling governs retinal cell specification and differentiation, and maintains retinal lamination as well, which is achieved probably through the expression of β-catenin
Summary
The highly ordered vertebrate retina is composed of seven cell types derived from a common pool of retinal progenitor cells (RPCs), and is a good model for the studies of cell differentiation and interaction during neural development. The canonical Notch pathway includes five ligands (Delta-like [Dll] 1, 3, 4, Jagged1, 2), four receptors (Notch1-4), and the transcription factor recombination signal-binding protein Jκ (RBP-J) ( termed CBF1 in mammals), which regulates the expression of downstream genes such as the Hairy and enhancer of split (Hes) family members. Both Notch ligands and receptors are type I transmembrane proteins mediating direct cell-cell interactions. Because RBP-J binds to NICD of all four mammalian Notch receptors, it serves as the key integrator of canonical Notch signaling [5,6]
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