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Can Replace Er81 Function in Controlling Ia Afferent Projections\nWe first defined an ETS transcription regulator that is able to replace the function of Er81 within proprioceptive afferents to direct projections into the ventral spinal cord. Er81, Pea3, and Erm constitute the Pea3 subfamily of ETS transcription factors, show a high degree of amino acid identity, and bind to very similar DNA target sequences [17,18,19]. Nevertheless, when introduced into the Er81 locus in analogy to a previously used targeting strategy (data not shown; [14]), neither Pea3 nor Erm could rescue Ia proprioceptive afferent projections to extensively invade the ventral horn of the spinal cord (data not shown). These findings prompted us to analyze mice in which we integrated EWS-Pea3, a break-point fusion product between the amino-terminal domain of the Ewing sarcoma (EWS) gene and the Pea3 DNA binding domain [20,21], into the Er81 locus (Figure 1). We found that in a luciferase-enzyme-based cell culture transfection assay, EWS-Pea3 showed stronger transactivation activity than Er81 or Pea3 (Figure 1J; data not shown), in agreement with previous studies [22,23,24]. Moreover, transactivation by EWS-Pea3 was abolished by mutation of ETS-binding sites in the reporter plasmid, demonstrating ETS-binding-site dependence (data not shown).\nFigure 1 Replacement of Er81 by EWS-Pea3\n(A) Generation of Er81EWS-Pea3 mutant mice. Above is the organization of the Er81 genomic locus in the region targeted by homologous recombination in analogy to [14]. Exons 1–4 are shown as light blue boxes, and the Er81 start codon in exon 2 is indicated as ATG. The probe used to detect homologous recombination is shown as a grey box. Below is replacement of Er81 by EWS-Pea3 through the integration of EWS-Pea3 in frame with the endogenous start codon of the Er81 locus in exon 2 (in analogy to [14]).\n(B) PCR and Southern blot analysis of Er81EWS-Pea3 wild-type (+/+), heterozygous (+/−), and homozygous (−/−) genomic DNA to detect the mutant allele. PCR primer pairs (EWS-Pea3ki) were used to detect specifically the recombined allele, and a primer pair in exon2 was used to detect the presence of the wild-type allele [14].\n(C–E) Analysis of Er81 expression in lumbar DRG neurons of E16.5 wild-type (C), Er81−/− (D), and Er81EWS-Pea3/− (E) embryos. Inset in lower right corner of each panel shows Isl1 expression in the respective DRG.\n(F–H) PV expression in lumbar DRG of E16.5 wild-type (F), Er81−/− (G), and Er81EWS-Pea3/− (H) embryos. Confocal scans were performed with equal gain intensity.\n(J) Transcriptional transactivation of luciferase expression from a minimal reporter construct containing five consensus ETS DNA-binding sites ( GCCGGAAGC; [18,19]) and a minimal TK promoter upon transient transfection of Er81 (n ≥ 7; 3.03 ± 0.66) or EWS-Pea3 (n ≥ 7; 20.3 ± 2.7). Relative luciferase activity normalized to control (Con).\nScale bar: 80 μm. Expression of Er81 in DRG neurons of embryos containing integration of EWS-Pea3 in the Er81 locus (Er81EWS-Pea3/−) was abolished (Figure 1E), and the expression level of the calcium-binding protein Parvalbumin (PV) in proprioceptive afferents, which is decreased approximately 5- to 10-fold in Er81 mutants [14], was comparable to wild-type levels in Er81EWS-Pea3/− embryos (Figure 1F–1H). To further define DRG neuron differentiation in the presence of EWS-Pea3 in proprioceptive afferents in vivo, we assessed whether replacement of Er81 by EWS-Pea3 had an influence on neuronal survival or on the expression of proprioceptive-afferent-specific genes. Er81EWS-Pea3/− mice did not differ from wild-type in the number of proprioceptive afferent cell bodies within the DRG of L1 to L5, the expression of several genes normally expressed by proprioceptive afferents, and the lack of expression of genes not normally expressed in proprioceptive afferents (Figure S1; data not shown). Together, these findings suggest that the expression of EWS-Pea3 from the normal time of onset mimics the function of Er81 as assessed by induction and maintenance of gene expression within proprioceptive afferents.\nTo determine the extent of rescue of Ia proprioceptive afferent projections into the ventral spinal cord of Er81 mutant mice achieved by expression of EWS-Pea3, we traced intraspinal afferent projections by axonal labeling of PV (Figure 2A–2C). In addition, to analyze axon ingrowth independent of the level of PV expression in DRG neurons, we used anterograde labeling of afferent fibers by applying fluorescently labeled dextran to cut dorsal roots (Figure 2D–2F). Using both assays, we found extensive rescue of the projections into the ventral horn of the spinal cord in Er81EWS-Pea3/− mice (Figure 2C and 2F). Within the ventral horn, Ia afferents in both wild-type and Er81EWS-Pea3/− mice formed vGlut1+ terminals that were absent in Er81 mutant mice (Figure 2G–2I). To assess whether synapses between Ia afferents and motor neurons are functional in Er81EWS-Pea3/− mice, we performed intracellular recordings from identified quadriceps motor neurons after stimulation of nerves innervating the quadriceps muscle group. We found no significant difference in the input amplitude to quadriceps motor neurons when comparing wild-type to Er81EWS-Pea3/− mice (Figure S2; wild-type, 10.6 ± 0.9 mV, n = 11; Er81EWS-Pea3/−, 10.9 ± 1 mV, n = 8). Together, these findings suggest that in the absence of Er81, EWS-Pea3 can direct the complex biological process of correct laminar termination within the ventral spinal cord and the formation of synapses with motor neurons (Figure 2J–2L), thus identifying an ETS transcription factor suitable for heterochronic expression experiments in DRG neurons.\nFigure 2 Rescue of Ia Proprioceptive Afferent Projections into the Ventral Spinal Cord in Er81EWS-Pea3 Mutants\n(A–F) Morphological analysis of central projections at lumbar level L3 of PV+ DRG neurons (A–C) or all DRG sensory afferents after application of fluorescently labeled dextran to individual dorsal roots (D–F) in P0.5 (A–C) or P5 (D–F) wild-type (A and D), Er81−/− (B and E), and Er81EWS-Pea3/− (C and F) mice. Red dotted line indicates intermediate level of spinal cord.\n(G–I) Analysis of vGlut1 immunocytochemistry in the ventral horn of P0.5 wild-type (G), Er81−/− (H), and Er81EWS-Pea3/− (I) mice. Yellow dotted box in (A) indicates size of images shown in (G–I).\n(J–L) Schematic summary diagrams of the morphological rescue of Ia proprioceptive afferent projections (blue) into the ventral spinal cord observed in wild-type (J), Er81−/− (K), and Er81EWS-Pea3/− (L) mice. DRG indicated by dotted grey line; motor neurons are shown in black.\nScale bar: (A–C), 150 μm; (D–F), 160 μm; (G–I), 70 μm."}

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Can Replace Er81 Function in Controlling Ia Afferent Projections\nWe first defined an ETS transcription regulator that is able to replace the function of Er81 within proprioceptive afferents to direct projections into the ventral spinal cord. Er81, Pea3, and Erm constitute the Pea3 subfamily of ETS transcription factors, show a high degree of amino acid identity, and bind to very similar DNA target sequences [17,18,19]. Nevertheless, when introduced into the Er81 locus in analogy to a previously used targeting strategy (data not shown; [14]), neither Pea3 nor Erm could rescue Ia proprioceptive afferent projections to extensively invade the ventral horn of the spinal cord (data not shown). These findings prompted us to analyze mice in which we integrated EWS-Pea3, a break-point fusion product between the amino-terminal domain of the Ewing sarcoma (EWS) gene and the Pea3 DNA binding domain [20,21], into the Er81 locus (Figure 1). We found that in a luciferase-enzyme-based cell culture transfection assay, EWS-Pea3 showed stronger transactivation activity than Er81 or Pea3 (Figure 1J; data not shown), in agreement with previous studies [22,23,24]. Moreover, transactivation by EWS-Pea3 was abolished by mutation of ETS-binding sites in the reporter plasmid, demonstrating ETS-binding-site dependence (data not shown).\nFigure 1 Replacement of Er81 by EWS-Pea3\n(A) Generation of Er81EWS-Pea3 mutant mice. Above is the organization of the Er81 genomic locus in the region targeted by homologous recombination in analogy to [14]. Exons 1–4 are shown as light blue boxes, and the Er81 start codon in exon 2 is indicated as ATG. The probe used to detect homologous recombination is shown as a grey box. Below is replacement of Er81 by EWS-Pea3 through the integration of EWS-Pea3 in frame with the endogenous start codon of the Er81 locus in exon 2 (in analogy to [14]).\n(B) PCR and Southern blot analysis of Er81EWS-Pea3 wild-type (+/+), heterozygous (+/−), and homozygous (−/−) genomic DNA to detect the mutant allele. PCR primer pairs (EWS-Pea3ki) were used to detect specifically the recombined allele, and a primer pair in exon2 was used to detect the presence of the wild-type allele [14].\n(C–E) Analysis of Er81 expression in lumbar DRG neurons of E16.5 wild-type (C), Er81−/− (D), and Er81EWS-Pea3/− (E) embryos. Inset in lower right corner of each panel shows Isl1 expression in the respective DRG.\n(F–H) PV expression in lumbar DRG of E16.5 wild-type (F), Er81−/− (G), and Er81EWS-Pea3/− (H) embryos. Confocal scans were performed with equal gain intensity.\n(J) Transcriptional transactivation of luciferase expression from a minimal reporter construct containing five consensus ETS DNA-binding sites ( GCCGGAAGC; [18,19]) and a minimal TK promoter upon transient transfection of Er81 (n ≥ 7; 3.03 ± 0.66) or EWS-Pea3 (n ≥ 7; 20.3 ± 2.7). Relative luciferase activity normalized to control (Con).\nScale bar: 80 μm. Expression of Er81 in DRG neurons of embryos containing integration of EWS-Pea3 in the Er81 locus (Er81EWS-Pea3/−) was abolished (Figure 1E), and the expression level of the calcium-binding protein Parvalbumin (PV) in proprioceptive afferents, which is decreased approximately 5- to 10-fold in Er81 mutants [14], was comparable to wild-type levels in Er81EWS-Pea3/− embryos (Figure 1F–1H). To further define DRG neuron differentiation in the presence of EWS-Pea3 in proprioceptive afferents in vivo, we assessed whether replacement of Er81 by EWS-Pea3 had an influence on neuronal survival or on the expression of proprioceptive-afferent-specific genes. Er81EWS-Pea3/− mice did not differ from wild-type in the number of proprioceptive afferent cell bodies within the DRG of L1 to L5, the expression of several genes normally expressed by proprioceptive afferents, and the lack of expression of genes not normally expressed in proprioceptive afferents (Figure S1; data not shown). Together, these findings suggest that the expression of EWS-Pea3 from the normal time of onset mimics the function of Er81 as assessed by induction and maintenance of gene expression within proprioceptive afferents.\nTo determine the extent of rescue of Ia proprioceptive afferent projections into the ventral spinal cord of Er81 mutant mice achieved by expression of EWS-Pea3, we traced intraspinal afferent projections by axonal labeling of PV (Figure 2A–2C). In addition, to analyze axon ingrowth independent of the level of PV expression in DRG neurons, we used anterograde labeling of afferent fibers by applying fluorescently labeled dextran to cut dorsal roots (Figure 2D–2F). Using both assays, we found extensive rescue of the projections into the ventral horn of the spinal cord in Er81EWS-Pea3/− mice (Figure 2C and 2F). Within the ventral horn, Ia afferents in both wild-type and Er81EWS-Pea3/− mice formed vGlut1+ terminals that were absent in Er81 mutant mice (Figure 2G–2I). To assess whether synapses between Ia afferents and motor neurons are functional in Er81EWS-Pea3/− mice, we performed intracellular recordings from identified quadriceps motor neurons after stimulation of nerves innervating the quadriceps muscle group. We found no significant difference in the input amplitude to quadriceps motor neurons when comparing wild-type to Er81EWS-Pea3/− mice (Figure S2; wild-type, 10.6 ± 0.9 mV, n = 11; Er81EWS-Pea3/−, 10.9 ± 1 mV, n = 8). Together, these findings suggest that in the absence of Er81, EWS-Pea3 can direct the complex biological process of correct laminar termination within the ventral spinal cord and the formation of synapses with motor neurons (Figure 2J–2L), thus identifying an ETS transcription factor suitable for heterochronic expression experiments in DRG neurons.\nFigure 2 Rescue of Ia Proprioceptive Afferent Projections into the Ventral Spinal Cord in Er81EWS-Pea3 Mutants\n(A–F) Morphological analysis of central projections at lumbar level L3 of PV+ DRG neurons (A–C) or all DRG sensory afferents after application of fluorescently labeled dextran to individual dorsal roots (D–F) in P0.5 (A–C) or P5 (D–F) wild-type (A and D), Er81−/− (B and E), and Er81EWS-Pea3/− (C and F) mice. Red dotted line indicates intermediate level of spinal cord.\n(G–I) Analysis of vGlut1 immunocytochemistry in the ventral horn of P0.5 wild-type (G), Er81−/− (H), and Er81EWS-Pea3/− (I) mice. Yellow dotted box in (A) indicates size of images shown in (G–I).\n(J–L) Schematic summary diagrams of the morphological rescue of Ia proprioceptive afferent projections (blue) into the ventral spinal cord observed in wild-type (J), Er81−/− (K), and Er81EWS-Pea3/− (L) mice. DRG indicated by dotted grey line; motor neurons are shown in black.\nScale bar: (A–C), 150 μm; (D–F), 160 μm; (G–I), 70 μm."}

{"project":"2_test","denotations":[{"id":"15836427-9259977-84719619","span":{"begin":421,"end":423},"obj":"9259977"},{"id":"15836427-9734357-84719620","span":{"begin":424,"end":426},"obj":"9734357"},{"id":"15836427-11096072-84719621","span":{"begin":427,"end":429},"obj":"11096072"},{"id":"15836427-10850491-84719622","span":{"begin":551,"end":553},"obj":"10850491"},{"id":"15836427-8605035-84719623","span":{"begin":910,"end":912},"obj":"8605035"},{"id":"15836427-11607824-84719624","span":{"begin":913,"end":915},"obj":"11607824"},{"id":"15836427-8246959-84719625","span":{"begin":1159,"end":1161},"obj":"8246959"},{"id":"15836427-7503813-84719626","span":{"begin":1162,"end":1164},"obj":"7503813"},{"id":"15836427-10623711-84719627","span":{"begin":1165,"end":1167},"obj":"10623711"},{"id":"15836427-10850491-84719628","span":{"begin":1544,"end":1546},"obj":"10850491"},{"id":"15836427-10850491-84719629","span":{"begin":1882,"end":1884},"obj":"10850491"},{"id":"15836427-10850491-84719630","span":{"begin":2208,"end":2210},"obj":"10850491"},{"id":"15836427-9734357-84719631","span":{"begin":2742,"end":2744},"obj":"9734357"},{"id":"15836427-11096072-84719632","span":{"begin":2745,"end":2747},"obj":"11096072"},{"id":"15836427-10850491-84719633","span":{"begin":3250,"end":3252},"obj":"10850491"},{"id":"T23891","span":{"begin":421,"end":423},"obj":"9259977"},{"id":"T38448","span":{"begin":424,"end":426},"obj":"9734357"},{"id":"T25362","span":{"begin":427,"end":429},"obj":"11096072"},{"id":"T88334","span":{"begin":551,"end":553},"obj":"10850491"},{"id":"T1568","span":{"begin":910,"end":912},"obj":"8605035"},{"id":"T23957","span":{"begin":913,"end":915},"obj":"11607824"},{"id":"T9762","span":{"begin":1159,"end":1161},"obj":"8246959"},{"id":"T92554","span":{"begin":1162,"end":1164},"obj":"7503813"},{"id":"T11355","span":{"begin":1165,"end":1167},"obj":"10623711"},{"id":"T40480","span":{"begin":1544,"end":1546},"obj":"10850491"},{"id":"T21606","span":{"begin":1882,"end":1884},"obj":"10850491"},{"id":"T94600","span":{"begin":2208,"end":2210},"obj":"10850491"},{"id":"T96846","span":{"begin":2742,"end":2744},"obj":"9734357"},{"id":"T64151","span":{"begin":2745,"end":2747},"obj":"11096072"},{"id":"T5880","span":{"begin":3250,"end":3252},"obj":"10850491"}],"text":"EWS-Pea3 Can Replace Er81 Function in Controlling Ia Afferent Projections\nWe first defined an ETS transcription regulator that is able to replace the function of Er81 within proprioceptive afferents to direct projections into the ventral spinal cord. Er81, Pea3, and Erm constitute the Pea3 subfamily of ETS transcription factors, show a high degree of amino acid identity, and bind to very similar DNA target sequences [17,18,19]. Nevertheless, when introduced into the Er81 locus in analogy to a previously used targeting strategy (data not shown; [14]), neither Pea3 nor Erm could rescue Ia proprioceptive afferent projections to extensively invade the ventral horn of the spinal cord (data not shown). These findings prompted us to analyze mice in which we integrated EWS-Pea3, a break-point fusion product between the amino-terminal domain of the Ewing sarcoma (EWS) gene and the Pea3 DNA binding domain [20,21], into the Er81 locus (Figure 1). We found that in a luciferase-enzyme-based cell culture transfection assay, EWS-Pea3 showed stronger transactivation activity than Er81 or Pea3 (Figure 1J; data not shown), in agreement with previous studies [22,23,24]. Moreover, transactivation by EWS-Pea3 was abolished by mutation of ETS-binding sites in the reporter plasmid, demonstrating ETS-binding-site dependence (data not shown).\nFigure 1 Replacement of Er81 by EWS-Pea3\n(A) Generation of Er81EWS-Pea3 mutant mice. Above is the organization of the Er81 genomic locus in the region targeted by homologous recombination in analogy to [14]. Exons 1–4 are shown as light blue boxes, and the Er81 start codon in exon 2 is indicated as ATG. The probe used to detect homologous recombination is shown as a grey box. Below is replacement of Er81 by EWS-Pea3 through the integration of EWS-Pea3 in frame with the endogenous start codon of the Er81 locus in exon 2 (in analogy to [14]).\n(B) PCR and Southern blot analysis of Er81EWS-Pea3 wild-type (+/+), heterozygous (+/−), and homozygous (−/−) genomic DNA to detect the mutant allele. PCR primer pairs (EWS-Pea3ki) were used to detect specifically the recombined allele, and a primer pair in exon2 was used to detect the presence of the wild-type allele [14].\n(C–E) Analysis of Er81 expression in lumbar DRG neurons of E16.5 wild-type (C), Er81−/− (D), and Er81EWS-Pea3/− (E) embryos. Inset in lower right corner of each panel shows Isl1 expression in the respective DRG.\n(F–H) PV expression in lumbar DRG of E16.5 wild-type (F), Er81−/− (G), and Er81EWS-Pea3/− (H) embryos. Confocal scans were performed with equal gain intensity.\n(J) Transcriptional transactivation of luciferase expression from a minimal reporter construct containing five consensus ETS DNA-binding sites ( GCCGGAAGC; [18,19]) and a minimal TK promoter upon transient transfection of Er81 (n ≥ 7; 3.03 ± 0.66) or EWS-Pea3 (n ≥ 7; 20.3 ± 2.7). Relative luciferase activity normalized to control (Con).\nScale bar: 80 μm. Expression of Er81 in DRG neurons of embryos containing integration of EWS-Pea3 in the Er81 locus (Er81EWS-Pea3/−) was abolished (Figure 1E), and the expression level of the calcium-binding protein Parvalbumin (PV) in proprioceptive afferents, which is decreased approximately 5- to 10-fold in Er81 mutants [14], was comparable to wild-type levels in Er81EWS-Pea3/− embryos (Figure 1F–1H). To further define DRG neuron differentiation in the presence of EWS-Pea3 in proprioceptive afferents in vivo, we assessed whether replacement of Er81 by EWS-Pea3 had an influence on neuronal survival or on the expression of proprioceptive-afferent-specific genes. Er81EWS-Pea3/− mice did not differ from wild-type in the number of proprioceptive afferent cell bodies within the DRG of L1 to L5, the expression of several genes normally expressed by proprioceptive afferents, and the lack of expression of genes not normally expressed in proprioceptive afferents (Figure S1; data not shown). Together, these findings suggest that the expression of EWS-Pea3 from the normal time of onset mimics the function of Er81 as assessed by induction and maintenance of gene expression within proprioceptive afferents.\nTo determine the extent of rescue of Ia proprioceptive afferent projections into the ventral spinal cord of Er81 mutant mice achieved by expression of EWS-Pea3, we traced intraspinal afferent projections by axonal labeling of PV (Figure 2A–2C). In addition, to analyze axon ingrowth independent of the level of PV expression in DRG neurons, we used anterograde labeling of afferent fibers by applying fluorescently labeled dextran to cut dorsal roots (Figure 2D–2F). Using both assays, we found extensive rescue of the projections into the ventral horn of the spinal cord in Er81EWS-Pea3/− mice (Figure 2C and 2F). Within the ventral horn, Ia afferents in both wild-type and Er81EWS-Pea3/− mice formed vGlut1+ terminals that were absent in Er81 mutant mice (Figure 2G–2I). To assess whether synapses between Ia afferents and motor neurons are functional in Er81EWS-Pea3/− mice, we performed intracellular recordings from identified quadriceps motor neurons after stimulation of nerves innervating the quadriceps muscle group. We found no significant difference in the input amplitude to quadriceps motor neurons when comparing wild-type to Er81EWS-Pea3/− mice (Figure S2; wild-type, 10.6 ± 0.9 mV, n = 11; Er81EWS-Pea3/−, 10.9 ± 1 mV, n = 8). Together, these findings suggest that in the absence of Er81, EWS-Pea3 can direct the complex biological process of correct laminar termination within the ventral spinal cord and the formation of synapses with motor neurons (Figure 2J–2L), thus identifying an ETS transcription factor suitable for heterochronic expression experiments in DRG neurons.\nFigure 2 Rescue of Ia Proprioceptive Afferent Projections into the Ventral Spinal Cord in Er81EWS-Pea3 Mutants\n(A–F) Morphological analysis of central projections at lumbar level L3 of PV+ DRG neurons (A–C) or all DRG sensory afferents after application of fluorescently labeled dextran to individual dorsal roots (D–F) in P0.5 (A–C) or P5 (D–F) wild-type (A and D), Er81−/− (B and E), and Er81EWS-Pea3/− (C and F) mice. Red dotted line indicates intermediate level of spinal cord.\n(G–I) Analysis of vGlut1 immunocytochemistry in the ventral horn of P0.5 wild-type (G), Er81−/− (H), and Er81EWS-Pea3/− (I) mice. Yellow dotted box in (A) indicates size of images shown in (G–I).\n(J–L) Schematic summary diagrams of the morphological rescue of Ia proprioceptive afferent projections (blue) into the ventral spinal cord observed in wild-type (J), Er81−/− (K), and Er81EWS-Pea3/− (L) mice. DRG indicated by dotted grey line; motor neurons are shown in black.\nScale bar: (A–C), 150 μm; (D–F), 160 μm; (G–I), 70 μm."}

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Can Replace Er81 Function in Controlling Ia Afferent Projections\nWe first defined an ETS transcription regulator that is able to replace the function of Er81 within proprioceptive afferents to direct projections into the ventral spinal cord. Er81, Pea3, and Erm constitute the Pea3 subfamily of ETS transcription factors, show a high degree of amino acid identity, and bind to very similar DNA target sequences [17,18,19]. Nevertheless, when introduced into the Er81 locus in analogy to a previously used targeting strategy (data not shown; [14]), neither Pea3 nor Erm could rescue Ia proprioceptive afferent projections to extensively invade the ventral horn of the spinal cord (data not shown). These findings prompted us to analyze mice in which we integrated EWS-Pea3, a break-point fusion product between the amino-terminal domain of the Ewing sarcoma (EWS) gene and the Pea3 DNA binding domain [20,21], into the Er81 locus (Figure 1). We found that in a luciferase-enzyme-based cell culture transfection assay, EWS-Pea3 showed stronger transactivation activity than Er81 or Pea3 (Figure 1J; data not shown), in agreement with previous studies [22,23,24]. Moreover, transactivation by EWS-Pea3 was abolished by mutation of ETS-binding sites in the reporter plasmid, demonstrating ETS-binding-site dependence (data not shown).\nFigure 1 Replacement of Er81 by EWS-Pea3\n(A) Generation of Er81EWS-Pea3 mutant mice. Above is the organization of the Er81 genomic locus in the region targeted by homologous recombination in analogy to [14]. Exons 1–4 are shown as light blue boxes, and the Er81 start codon in exon 2 is indicated as ATG. The probe used to detect homologous recombination is shown as a grey box. Below is replacement of Er81 by EWS-Pea3 through the integration of EWS-Pea3 in frame with the endogenous start codon of the Er81 locus in exon 2 (in analogy to [14]).\n(B) PCR and Southern blot analysis of Er81EWS-Pea3 wild-type (+/+), heterozygous (+/−), and homozygous (−/−) genomic DNA to detect the mutant allele. PCR primer pairs (EWS-Pea3ki) were used to detect specifically the recombined allele, and a primer pair in exon2 was used to detect the presence of the wild-type allele [14].\n(C–E) Analysis of Er81 expression in lumbar DRG neurons of E16.5 wild-type (C), Er81−/− (D), and Er81EWS-Pea3/− (E) embryos. Inset in lower right corner of each panel shows Isl1 expression in the respective DRG.\n(F–H) PV expression in lumbar DRG of E16.5 wild-type (F), Er81−/− (G), and Er81EWS-Pea3/− (H) embryos. Confocal scans were performed with equal gain intensity.\n(J) Transcriptional transactivation of luciferase expression from a minimal reporter construct containing five consensus ETS DNA-binding sites ( GCCGGAAGC; [18,19]) and a minimal TK promoter upon transient transfection of Er81 (n ≥ 7; 3.03 ± 0.66) or EWS-Pea3 (n ≥ 7; 20.3 ± 2.7). Relative luciferase activity normalized to control (Con).\nScale bar: 80 μm. Expression of Er81 in DRG neurons of embryos containing integration of EWS-Pea3 in the Er81 locus (Er81EWS-Pea3/−) was abolished (Figure 1E), and the expression level of the calcium-binding protein Parvalbumin (PV) in proprioceptive afferents, which is decreased approximately 5- to 10-fold in Er81 mutants [14], was comparable to wild-type levels in Er81EWS-Pea3/− embryos (Figure 1F–1H). To further define DRG neuron differentiation in the presence of EWS-Pea3 in proprioceptive afferents in vivo, we assessed whether replacement of Er81 by EWS-Pea3 had an influence on neuronal survival or on the expression of proprioceptive-afferent-specific genes. Er81EWS-Pea3/− mice did not differ from wild-type in the number of proprioceptive afferent cell bodies within the DRG of L1 to L5, the expression of several genes normally expressed by proprioceptive afferents, and the lack of expression of genes not normally expressed in proprioceptive afferents (Figure S1; data not shown). Together, these findings suggest that the expression of EWS-Pea3 from the normal time of onset mimics the function of Er81 as assessed by induction and maintenance of gene expression within proprioceptive afferents.\nTo determine the extent of rescue of Ia proprioceptive afferent projections into the ventral spinal cord of Er81 mutant mice achieved by expression of EWS-Pea3, we traced intraspinal afferent projections by axonal labeling of PV (Figure 2A–2C). In addition, to analyze axon ingrowth independent of the level of PV expression in DRG neurons, we used anterograde labeling of afferent fibers by applying fluorescently labeled dextran to cut dorsal roots (Figure 2D–2F). Using both assays, we found extensive rescue of the projections into the ventral horn of the spinal cord in Er81EWS-Pea3/− mice (Figure 2C and 2F). Within the ventral horn, Ia afferents in both wild-type and Er81EWS-Pea3/− mice formed vGlut1+ terminals that were absent in Er81 mutant mice (Figure 2G–2I). To assess whether synapses between Ia afferents and motor neurons are functional in Er81EWS-Pea3/− mice, we performed intracellular recordings from identified quadriceps motor neurons after stimulation of nerves innervating the quadriceps muscle group. We found no significant difference in the input amplitude to quadriceps motor neurons when comparing wild-type to Er81EWS-Pea3/− mice (Figure S2; wild-type, 10.6 ± 0.9 mV, n = 11; Er81EWS-Pea3/−, 10.9 ± 1 mV, n = 8). Together, these findings suggest that in the absence of Er81, EWS-Pea3 can direct the complex biological process of correct laminar termination within the ventral spinal cord and the formation of synapses with motor neurons (Figure 2J–2L), thus identifying an ETS transcription factor suitable for heterochronic expression experiments in DRG neurons.\nFigure 2 Rescue of Ia Proprioceptive Afferent Projections into the Ventral Spinal Cord in Er81EWS-Pea3 Mutants\n(A–F) Morphological analysis of central projections at lumbar level L3 of PV+ DRG neurons (A–C) or all DRG sensory afferents after application of fluorescently labeled dextran to individual dorsal roots (D–F) in P0.5 (A–C) or P5 (D–F) wild-type (A and D), Er81−/− (B and E), and Er81EWS-Pea3/− (C and F) mice. Red dotted line indicates intermediate level of spinal cord.\n(G–I) Analysis of vGlut1 immunocytochemistry in the ventral horn of P0.5 wild-type (G), Er81−/− (H), and Er81EWS-Pea3/− (I) mice. Yellow dotted box in (A) indicates size of images shown in (G–I).\n(J–L) Schematic summary diagrams of the morphological rescue of Ia proprioceptive afferent projections (blue) into the ventral spinal cord observed in wild-type (J), Er81−/− (K), and Er81EWS-Pea3/− (L) mice. DRG indicated by dotted grey line; motor neurons are shown in black.\nScale bar: (A–C), 150 μm; (D–F), 160 μm; (G–I), 70 μm."}

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Can Replace Er81 Function in Controlling Ia Afferent Projections\nWe first defined an ETS transcription regulator that is able to replace the function of Er81 within proprioceptive afferents to direct projections into the ventral spinal cord. Er81, Pea3, and Erm constitute the Pea3 subfamily of ETS transcription factors, show a high degree of amino acid identity, and bind to very similar DNA target sequences [17,18,19]. Nevertheless, when introduced into the Er81 locus in analogy to a previously used targeting strategy (data not shown; [14]), neither Pea3 nor Erm could rescue Ia proprioceptive afferent projections to extensively invade the ventral horn of the spinal cord (data not shown). These findings prompted us to analyze mice in which we integrated EWS-Pea3, a break-point fusion product between the amino-terminal domain of the Ewing sarcoma (EWS) gene and the Pea3 DNA binding domain [20,21], into the Er81 locus (Figure 1). We found that in a luciferase-enzyme-based cell culture transfection assay, EWS-Pea3 showed stronger transactivation activity than Er81 or Pea3 (Figure 1J; data not shown), in agreement with previous studies [22,23,24]. Moreover, transactivation by EWS-Pea3 was abolished by mutation of ETS-binding sites in the reporter plasmid, demonstrating ETS-binding-site dependence (data not shown).\nFigure 1 Replacement of Er81 by EWS-Pea3\n(A) Generation of Er81EWS-Pea3 mutant mice. Above is the organization of the Er81 genomic locus in the region targeted by homologous recombination in analogy to [14]. Exons 1–4 are shown as light blue boxes, and the Er81 start codon in exon 2 is indicated as ATG. The probe used to detect homologous recombination is shown as a grey box. Below is replacement of Er81 by EWS-Pea3 through the integration of EWS-Pea3 in frame with the endogenous start codon of the Er81 locus in exon 2 (in analogy to [14]).\n(B) PCR and Southern blot analysis of Er81EWS-Pea3 wild-type (+/+), heterozygous (+/−), and homozygous (−/−) genomic DNA to detect the mutant allele. PCR primer pairs (EWS-Pea3ki) were used to detect specifically the recombined allele, and a primer pair in exon2 was used to detect the presence of the wild-type allele [14].\n(C–E) Analysis of Er81 expression in lumbar DRG neurons of E16.5 wild-type (C), Er81−/− (D), and Er81EWS-Pea3/− (E) embryos. Inset in lower right corner of each panel shows Isl1 expression in the respective DRG.\n(F–H) PV expression in lumbar DRG of E16.5 wild-type (F), Er81−/− (G), and Er81EWS-Pea3/− (H) embryos. Confocal scans were performed with equal gain intensity.\n(J) Transcriptional transactivation of luciferase expression from a minimal reporter construct containing five consensus ETS DNA-binding sites ( GCCGGAAGC; [18,19]) and a minimal TK promoter upon transient transfection of Er81 (n ≥ 7; 3.03 ± 0.66) or EWS-Pea3 (n ≥ 7; 20.3 ± 2.7). Relative luciferase activity normalized to control (Con).\nScale bar: 80 μm. Expression of Er81 in DRG neurons of embryos containing integration of EWS-Pea3 in the Er81 locus (Er81EWS-Pea3/−) was abolished (Figure 1E), and the expression level of the calcium-binding protein Parvalbumin (PV) in proprioceptive afferents, which is decreased approximately 5- to 10-fold in Er81 mutants [14], was comparable to wild-type levels in Er81EWS-Pea3/− embryos (Figure 1F–1H). To further define DRG neuron differentiation in the presence of EWS-Pea3 in proprioceptive afferents in vivo, we assessed whether replacement of Er81 by EWS-Pea3 had an influence on neuronal survival or on the expression of proprioceptive-afferent-specific genes. Er81EWS-Pea3/− mice did not differ from wild-type in the number of proprioceptive afferent cell bodies within the DRG of L1 to L5, the expression of several genes normally expressed by proprioceptive afferents, and the lack of expression of genes not normally expressed in proprioceptive afferents (Figure S1; data not shown). Together, these findings suggest that the expression of EWS-Pea3 from the normal time of onset mimics the function of Er81 as assessed by induction and maintenance of gene expression within proprioceptive afferents.\nTo determine the extent of rescue of Ia proprioceptive afferent projections into the ventral spinal cord of Er81 mutant mice achieved by expression of EWS-Pea3, we traced intraspinal afferent projections by axonal labeling of PV (Figure 2A–2C). In addition, to analyze axon ingrowth independent of the level of PV expression in DRG neurons, we used anterograde labeling of afferent fibers by applying fluorescently labeled dextran to cut dorsal roots (Figure 2D–2F). Using both assays, we found extensive rescue of the projections into the ventral horn of the spinal cord in Er81EWS-Pea3/− mice (Figure 2C and 2F). Within the ventral horn, Ia afferents in both wild-type and Er81EWS-Pea3/− mice formed vGlut1+ terminals that were absent in Er81 mutant mice (Figure 2G–2I). To assess whether synapses between Ia afferents and motor neurons are functional in Er81EWS-Pea3/− mice, we performed intracellular recordings from identified quadriceps motor neurons after stimulation of nerves innervating the quadriceps muscle group. We found no significant difference in the input amplitude to quadriceps motor neurons when comparing wild-type to Er81EWS-Pea3/− mice (Figure S2; wild-type, 10.6 ± 0.9 mV, n = 11; Er81EWS-Pea3/−, 10.9 ± 1 mV, n = 8). Together, these findings suggest that in the absence of Er81, EWS-Pea3 can direct the complex biological process of correct laminar termination within the ventral spinal cord and the formation of synapses with motor neurons (Figure 2J–2L), thus identifying an ETS transcription factor suitable for heterochronic expression experiments in DRG neurons.\nFigure 2 Rescue of Ia Proprioceptive Afferent Projections into the Ventral Spinal Cord in Er81EWS-Pea3 Mutants\n(A–F) Morphological analysis of central projections at lumbar level L3 of PV+ DRG neurons (A–C) or all DRG sensory afferents after application of fluorescently labeled dextran to individual dorsal roots (D–F) in P0.5 (A–C) or P5 (D–F) wild-type (A and D), Er81−/− (B and E), and Er81EWS-Pea3/− (C and F) mice. Red dotted line indicates intermediate level of spinal cord.\n(G–I) Analysis of vGlut1 immunocytochemistry in the ventral horn of P0.5 wild-type (G), Er81−/− (H), and Er81EWS-Pea3/− (I) mice. Yellow dotted box in (A) indicates size of images shown in (G–I).\n(J–L) Schematic summary diagrams of the morphological rescue of Ia proprioceptive afferent projections (blue) into the ventral spinal cord observed in wild-type (J), Er81−/− (K), and Er81EWS-Pea3/− (L) mice. DRG indicated by dotted grey line; motor neurons are shown in black.\nScale bar: (A–C), 150 μm; (D–F), 160 μm; (G–I), 70 μm."}