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Controls SAC Differentiation through E2f3a\nComprehensive marker analysis revealed that, in striking contrast to other retinal neurons, E2f1 deletion did not suppress defects in Rb KO cholinergic SACs. Instead, we observed E2f1-independent defects in the synthesis and transport of a large cohort of SAC proteins. These data expand insight into the development of these important interneurons, but more critically, provide to our knowledge the first unambiguous evidence that Rb regulates neurogenesis beyond terminal mitosis. Rb binds more than 100 factors [43], and in several non-neuronal cells, such as skeletal muscle, adipocytes, and bone, it binds and potentiates tissue-specific transcription factors that promote differentiation [31–33]. The idea that Rb promotes muscle differentiation by potentiating Myod1 activity was contested [61], and other mechanisms proposed [62,63], but not involving E2f repression. Strikingly, however, we discovered that Rb promotes SAC differentiation through E2f3 (Figure 8).\nFigure 8 Rb Regulates Distinct Processes through E2f1 and E2f3a\nRed text and arrows indicate Rb-dependent events. Black text and arrows indicate events for which there is no direct evidence of Rb involvement. Rb does not appear to temper RPC expansion and is not required for differentiation of RPCs into RTCs, but is essential to couple RTC birth to terminal mitosis, thus locking them out of cycle. Rb performs this function by inhibiting E2f1. Rb is also required for SAC differentiation, and in this case, acts by inhibiting E2f3a. There is no direct evidence that Rb is required for terminal differentiation of other cell types. Colour codes and abbreviations as in Figure 1A. Rb regulation of SAC differentiation through E2f3 was independent of its role in controlling division or death: E2f3 deletion rescued Rb KO SAC defects but did not suppress aberrant proliferation or death, whereas E2f1 deletion reversed abnormal proliferation and death but did not rescue SAC differentiation. Double labelling confirmed that E2f1 but not E2f3 deletion reversed Rb KO SAC division. Moreover, deleting E2f1, but not E2f3, reversed deregulated expression of cell cycle and apoptotic genes in the Rb KO retina. E2f3 is expressed in a subset of CNS neurons (this work) and drives specific cell-cycle–independent defects in Rb KO forebrain neurons [53]. Thus, E2f3 inhibition is the first, and may be the only, mechanism by which Rb participates directly in neuronal differentiation.\nTo further dissect the mechanism of action of Rb in SACs we determined the E2f3 isoform it targets to promote differentiation. E2f3b was the primary candidate, since Rb and E2f3b collaborate to repress targets in quiescent cells in vitro [19]. However, in the first work to our knowledge to examine the function of any E2f protein isoform in vivo, we made the surprising observation that Rb regulates SAC differentiation through E2f3a (Figure 8). Formally, we cannot exclude the possibility that deleting E2f3b might also rescue SAC differentiation, but definitive proof will require analysis of E2f3b null mice. Nevertheless, our data prove that Rb definitely regulates SAC differentiation through the activating E2f3 isoform."}

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Controls SAC Differentiation through E2f3a\nComprehensive marker analysis revealed that, in striking contrast to other retinal neurons, E2f1 deletion did not suppress defects in Rb KO cholinergic SACs. Instead, we observed E2f1-independent defects in the synthesis and transport of a large cohort of SAC proteins. These data expand insight into the development of these important interneurons, but more critically, provide to our knowledge the first unambiguous evidence that Rb regulates neurogenesis beyond terminal mitosis. Rb binds more than 100 factors [43], and in several non-neuronal cells, such as skeletal muscle, adipocytes, and bone, it binds and potentiates tissue-specific transcription factors that promote differentiation [31–33]. The idea that Rb promotes muscle differentiation by potentiating Myod1 activity was contested [61], and other mechanisms proposed [62,63], but not involving E2f repression. Strikingly, however, we discovered that Rb promotes SAC differentiation through E2f3 (Figure 8).\nFigure 8 Rb Regulates Distinct Processes through E2f1 and E2f3a\nRed text and arrows indicate Rb-dependent events. Black text and arrows indicate events for which there is no direct evidence of Rb involvement. Rb does not appear to temper RPC expansion and is not required for differentiation of RPCs into RTCs, but is essential to couple RTC birth to terminal mitosis, thus locking them out of cycle. Rb performs this function by inhibiting E2f1. Rb is also required for SAC differentiation, and in this case, acts by inhibiting E2f3a. There is no direct evidence that Rb is required for terminal differentiation of other cell types. Colour codes and abbreviations as in Figure 1A. Rb regulation of SAC differentiation through E2f3 was independent of its role in controlling division or death: E2f3 deletion rescued Rb KO SAC defects but did not suppress aberrant proliferation or death, whereas E2f1 deletion reversed abnormal proliferation and death but did not rescue SAC differentiation. Double labelling confirmed that E2f1 but not E2f3 deletion reversed Rb KO SAC division. Moreover, deleting E2f1, but not E2f3, reversed deregulated expression of cell cycle and apoptotic genes in the Rb KO retina. E2f3 is expressed in a subset of CNS neurons (this work) and drives specific cell-cycle–independent defects in Rb KO forebrain neurons [53]. Thus, E2f3 inhibition is the first, and may be the only, mechanism by which Rb participates directly in neuronal differentiation.\nTo further dissect the mechanism of action of Rb in SACs we determined the E2f3 isoform it targets to promote differentiation. E2f3b was the primary candidate, since Rb and E2f3b collaborate to repress targets in quiescent cells in vitro [19]. However, in the first work to our knowledge to examine the function of any E2f protein isoform in vivo, we made the surprising observation that Rb regulates SAC differentiation through E2f3a (Figure 8). Formally, we cannot exclude the possibility that deleting E2f3b might also rescue SAC differentiation, but definitive proof will require analysis of E2f3b null mice. Nevertheless, our data prove that Rb definitely regulates SAC differentiation through the activating E2f3 isoform."}

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Controls SAC Differentiation through E2f3a\nComprehensive marker analysis revealed that, in striking contrast to other retinal neurons, E2f1 deletion did not suppress defects in Rb KO cholinergic SACs. Instead, we observed E2f1-independent defects in the synthesis and transport of a large cohort of SAC proteins. These data expand insight into the development of these important interneurons, but more critically, provide to our knowledge the first unambiguous evidence that Rb regulates neurogenesis beyond terminal mitosis. Rb binds more than 100 factors [43], and in several non-neuronal cells, such as skeletal muscle, adipocytes, and bone, it binds and potentiates tissue-specific transcription factors that promote differentiation [31–33]. The idea that Rb promotes muscle differentiation by potentiating Myod1 activity was contested [61], and other mechanisms proposed [62,63], but not involving E2f repression. Strikingly, however, we discovered that Rb promotes SAC differentiation through E2f3 (Figure 8).\nFigure 8 Rb Regulates Distinct Processes through E2f1 and E2f3a\nRed text and arrows indicate Rb-dependent events. Black text and arrows indicate events for which there is no direct evidence of Rb involvement. Rb does not appear to temper RPC expansion and is not required for differentiation of RPCs into RTCs, but is essential to couple RTC birth to terminal mitosis, thus locking them out of cycle. Rb performs this function by inhibiting E2f1. Rb is also required for SAC differentiation, and in this case, acts by inhibiting E2f3a. There is no direct evidence that Rb is required for terminal differentiation of other cell types. Colour codes and abbreviations as in Figure 1A. Rb regulation of SAC differentiation through E2f3 was independent of its role in controlling division or death: E2f3 deletion rescued Rb KO SAC defects but did not suppress aberrant proliferation or death, whereas E2f1 deletion reversed abnormal proliferation and death but did not rescue SAC differentiation. Double labelling confirmed that E2f1 but not E2f3 deletion reversed Rb KO SAC division. Moreover, deleting E2f1, but not E2f3, reversed deregulated expression of cell cycle and apoptotic genes in the Rb KO retina. E2f3 is expressed in a subset of CNS neurons (this work) and drives specific cell-cycle–independent defects in Rb KO forebrain neurons [53]. Thus, E2f3 inhibition is the first, and may be the only, mechanism by which Rb participates directly in neuronal differentiation.\nTo further dissect the mechanism of action of Rb in SACs we determined the E2f3 isoform it targets to promote differentiation. E2f3b was the primary candidate, since Rb and E2f3b collaborate to repress targets in quiescent cells in vitro [19]. However, in the first work to our knowledge to examine the function of any E2f protein isoform in vivo, we made the surprising observation that Rb regulates SAC differentiation through E2f3a (Figure 8). Formally, we cannot exclude the possibility that deleting E2f3b might also rescue SAC differentiation, but definitive proof will require analysis of E2f3b null mice. Nevertheless, our data prove that Rb definitely regulates SAC differentiation through the activating E2f3 isoform."}

{"project":"2_test","denotations":[{"id":"17608565-11447760-84869019","span":{"begin":561,"end":563},"obj":"11447760"},{"id":"17608565-8381715-84869020","span":{"begin":741,"end":743},"obj":"8381715"},{"id":"17608565-11545733-84869020","span":{"begin":741,"end":743},"obj":"11545733"},{"id":"17608565-8946919-84869020","span":{"begin":741,"end":743},"obj":"8946919"},{"id":"17608565-10601020-84869021","span":{"begin":844,"end":846},"obj":"10601020"},{"id":"17608565-11684023-84869022","span":{"begin":880,"end":882},"obj":"11684023"},{"id":"17608565-11034201-84869023","span":{"begin":883,"end":885},"obj":"11034201"},{"id":"17608565-15175242-84869024","span":{"begin":2736,"end":2738},"obj":"15175242"},{"id":"T97762","span":{"begin":561,"end":563},"obj":"11447760"},{"id":"T62413","span":{"begin":741,"end":743},"obj":"8381715"},{"id":"T83034","span":{"begin":741,"end":743},"obj":"11545733"},{"id":"T20471","span":{"begin":741,"end":743},"obj":"8946919"},{"id":"T83077","span":{"begin":844,"end":846},"obj":"10601020"},{"id":"T32657","span":{"begin":880,"end":882},"obj":"11684023"},{"id":"T9102","span":{"begin":883,"end":885},"obj":"11034201"},{"id":"T68445","span":{"begin":2736,"end":2738},"obj":"15175242"}],"text":"Rb Controls SAC Differentiation through E2f3a\nComprehensive marker analysis revealed that, in striking contrast to other retinal neurons, E2f1 deletion did not suppress defects in Rb KO cholinergic SACs. Instead, we observed E2f1-independent defects in the synthesis and transport of a large cohort of SAC proteins. These data expand insight into the development of these important interneurons, but more critically, provide to our knowledge the first unambiguous evidence that Rb regulates neurogenesis beyond terminal mitosis. Rb binds more than 100 factors [43], and in several non-neuronal cells, such as skeletal muscle, adipocytes, and bone, it binds and potentiates tissue-specific transcription factors that promote differentiation [31–33]. The idea that Rb promotes muscle differentiation by potentiating Myod1 activity was contested [61], and other mechanisms proposed [62,63], but not involving E2f repression. Strikingly, however, we discovered that Rb promotes SAC differentiation through E2f3 (Figure 8).\nFigure 8 Rb Regulates Distinct Processes through E2f1 and E2f3a\nRed text and arrows indicate Rb-dependent events. Black text and arrows indicate events for which there is no direct evidence of Rb involvement. Rb does not appear to temper RPC expansion and is not required for differentiation of RPCs into RTCs, but is essential to couple RTC birth to terminal mitosis, thus locking them out of cycle. Rb performs this function by inhibiting E2f1. Rb is also required for SAC differentiation, and in this case, acts by inhibiting E2f3a. There is no direct evidence that Rb is required for terminal differentiation of other cell types. Colour codes and abbreviations as in Figure 1A. Rb regulation of SAC differentiation through E2f3 was independent of its role in controlling division or death: E2f3 deletion rescued Rb KO SAC defects but did not suppress aberrant proliferation or death, whereas E2f1 deletion reversed abnormal proliferation and death but did not rescue SAC differentiation. Double labelling confirmed that E2f1 but not E2f3 deletion reversed Rb KO SAC division. Moreover, deleting E2f1, but not E2f3, reversed deregulated expression of cell cycle and apoptotic genes in the Rb KO retina. E2f3 is expressed in a subset of CNS neurons (this work) and drives specific cell-cycle–independent defects in Rb KO forebrain neurons [53]. Thus, E2f3 inhibition is the first, and may be the only, mechanism by which Rb participates directly in neuronal differentiation.\nTo further dissect the mechanism of action of Rb in SACs we determined the E2f3 isoform it targets to promote differentiation. E2f3b was the primary candidate, since Rb and E2f3b collaborate to repress targets in quiescent cells in vitro [19]. However, in the first work to our knowledge to examine the function of any E2f protein isoform in vivo, we made the surprising observation that Rb regulates SAC differentiation through E2f3a (Figure 8). Formally, we cannot exclude the possibility that deleting E2f3b might also rescue SAC differentiation, but definitive proof will require analysis of E2f3b null mice. Nevertheless, our data prove that Rb definitely regulates SAC differentiation through the activating E2f3 isoform."}