Abstract
It has long been known that loss of the retinoblastoma protein (Rb) perturbs neural differentiation, but the underlying mechanism has never been solved. Rb absence impairs cell cycle exit and triggers death of some neurons, so differentiation defects may well be indirect. Indeed, we show that abnormalities in both differentiation and light-evoked electrophysiological responses in Rb-deficient retinal cells are rescued when ectopic division and apoptosis are blocked specifically by deleting E2f transcription factor (E2f) 1. However, comprehensive cell-type analysis of the rescued double-null retina exposed cell-cycle–independent differentiation defects specifically in starburst amacrine cells (SACs), cholinergic interneurons critical in direction selectivity and developmentally important rhythmic bursts. Typically, Rb is thought to block division by repressing E2fs, but to promote differentiation by potentiating tissue-specific factors. Remarkably, however, Rb promotes SAC differentiation by inhibiting E2f3 activity. Two E2f3 isoforms exist, and we find both in the developing retina, although intriguingly they show distinct subcellular distribution. E2f3b is thought to mediate Rb function in quiescent cells. However, in what is to our knowledge the first work to dissect E2f isoform function in vivo we show that Rb promotes SAC differentiation through E2f3a. These data reveal a mechanism through which Rb regulates neural differentiation directly, and, unexpectedly, it involves inhibition of E2f3a, not potentiation of tissue-specific factors.
Highlights
The simplicity of the retina makes it an ideal tissue to study neurogenesis
retinoblastoma protein (Rb) is thought to promote differentiation by potentiating tissue-specific transcription factors, differentiation defects in Rb null cells could be an indirect consequence of E2f transcription factor (E2f)-driven division and death
Rather than potentiating a cell-specific factor, Rb promotes starburst cell differentiation by inhibiting another E2f, E2f3a. This cell-cycle–independent activity broadens the importance of the Rb–E2f pathway, and suggests we should reassess its role in the differentiation of other cell types
Summary
Its development proceeds through three overlapping steps starting with retinal progenitor cell (RPC) proliferation, followed by birth of post-mitotic retinal transition cells (RTCs, referred to as precursors), and ending with terminal differentiation of seven major cell types (Figure 1A) [1]. RPCs are multipotent and exit the cell cycle to generate different RTCs at specific time periods in development [1]. This process of RTC ‘‘birth’’ requires coupling of differentiation and cell cycle exit. Rods and cones make up the outer nuclear layer (ONL); horizontal, bipolar, and amacrine cells, as well as Muller glia cell bodies, reside in the inner nuclear layer (INL); and ganglion and displaced amacrine cells form the ganglion cell layer (GCL) (Figure 1A). The outer plexiform layer (OPL) and inner plexiform layer (IPL) house synaptic connections separating the ONL/INL and INL/GCL, respectively
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