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Featured ArticleArticles, Neurobiology of Disease

Breathing without CO2 Chemosensitivity in Conditional Phox2b Mutants

Nelina Ramanantsoa, Marie-Rose Hirsch, Muriel Thoby-Brisson, Véronique Dubreuil, Julien Bouvier, Pierre-Louis Ruffault, Boris Matrot, Gilles Fortin, Jean-François Brunet, Jorge Gallego and Christo Goridis
Journal of Neuroscience 7 September 2011, 31 (36) 12880-12888; https://doi.org/10.1523/JNEUROSCI.1721-11.2011
Nelina Ramanantsoa
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Marie-Rose Hirsch
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Muriel Thoby-Brisson
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Véronique Dubreuil
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Julien Bouvier
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Pierre-Louis Ruffault
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Boris Matrot
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Gilles Fortin
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Jean-François Brunet
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Jorge Gallego
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Christo Goridis
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    Figure 1.

    Schematic of the wild-type Phox2b gene, the targeting construct, and the targeted Phox2b locus. From 5′ to 3′, the targeting vector contained a 5′ homology arm of 3.7 kb, a loxP site inserted into the second intron followed by a neomycin resistance cassette flanked by frt sites and mouse exon 3, a loxP site inserted 3′ of the mouse polyA signal followed by the mutated human PHOX2B exon 3, and a 3′ homology arm of 6.9 kb followed by a diphtheria toxin A chain (DTA) cassette. CDS, coding sequence; Ex1, exon1; UTR, untranslated region.

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    Figure 2.

    Loss of RTN neurons in conditional Phox2b27Alacki mutants. A–C, Combined in situ hybridization with an Atoh1 probe and immunohistochemistry with anti-Phox2b antibodies on transverse sections showing the loss of differentiated RTN neurons in control P2b27Alacki, Pgk:cre;P2b27Alacki, or Egr2cre;P2b27Alacki E14.5 embryos as indicated. A population of equally Atoh1;Phox2b double-positive cells dorsal of nVII (Dubreuil et al., 2009; Rose et al., 2009) has also disappeared in the mutants. D–F, Triple labeling for Phox2b (red), Islet1,2 and TH (green) showing depletion of Phox2b+, Islet1,2−, and TH− cells in the RTN region in Pgk:cre; P2b27Alacki or Egr2cre;P2b27Alacki E14.5 embryos, as indicated. G, Quantification of RTN neuron loss in E14.5 and P1 P2b27Alacki mutants expressing either Egr2cre or Pgk::cre as cre drivers. RTN neurons were identified either by Atoh1 expression or by positivity for Phox2b and absence of Islet1,2 or peripherin and TH. The horizontal lines above the bars indicate +SD of the means.

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    Figure 3.

    Slowed down respiratory-like rhythm unresponsive to a low pH challenge but a functional pre-BötC in hindbrain–spinal cord preparations from E16.5 Egr2cre;Phox2b27Alacki embryos. A, Integrated phrenic nerve discharges (C4) at pH 7.4 and pH 7.2 for an Egr2+/+;P2b27Alacki/+ control embryo. B, Same as A for an Egr2cre/+;P2b27Alacki/+ mutant embryo. C, Quantification of the burst frequencies for Egr2+/+;P2b27Alacki/+ (Egr2+/+) and Egr2cre/+;P2b27Alacki/ (Egr2Cre/+) embryos as indicated. D, Left, Calcium imaging showing bilateral peak fluorescence changes during one burst of activity of the pre-BötC in a Egr2+/+;P2b27Alacki/+ transverse medullary slice loaded with Calcium Green-1 AM. Scale bar, .25 mm. Right, Trace showing rhythmic relative fluorescence changes (ΔF/F). E, Same as D for an Egr2cre/+;P2b27Alacki/+ mutant embryo. F, Quantification of the frequency of rhythmic bursts in the control (Egr2+/+) and mutant (Egr2Cre/+) pre-BötC as indicated. ns, Not significant.

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    Figure 4.

    Lack of CO2 chemosensitivity in young postnatal Egr2cre;P2b27Alacki mice and partial recovery in adulthood. A, Representative examples of plethysmographic recordings of P2 mutant and control mice in air and in response to 8% CO2. B, Same as A for P9 mice. C–F, Left, Mean values of ventilation (VE) in air or in response to 8% CO2 (shaded area) in mutant mice (black circles) and their control littermates (white circles) on P2 (n = 10 and n = 13 for mutants and controls, respectively), P9 (n = 9 and n = 13, respectively), P22 (n = 12 and n = 8, respectively), and adulthood (4 months old, n = 9 for both conditions). Each circle represents the mean ± SEM over a 30 s period. Middle, Ventilatory responses to hypercapnia expressed as the percentage VE change relative to baseline average VE, using the formula 100 × (peak VE − baseline VE)/ baseline VE. The peak VE response to hypercapnia was determined over the entire hypercapnic exposure. Right, Mean values of tidal volumes (VT) and breath durations (TTOT) in air or in response to 8% CO2 (shaded area) in mutant mice (black circles) and their control littermates (white circles) from which the VE values in the left panels have been calculated. At P2, baseline ventilation was lower in mutants than in controls because of longer breath duration, but had almost normalized at P9. Mutants did not increase VE in response to hypercapnia until a small response appeared on P22 and consolidated in adulthood, still blunted compared with controls.

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    Figure 5.

    Ventilatory responses of Egr2cre;P2b27Alacki mice to hypoxia. A, Mean values of ventilation (VE) in air and in response to hypoxia (10% O2, shaded area) of P4 mutant mice (black circles; n = 10) and their control littermates (white circles; n = 13). Each circle represents the mean ± SEM over a 30 s period. B, VE, TTOT, and VT values expressed as percentage change relative to baseline ventilation as indicated. The mutants show a more vigorous and sustained ventilatory response, mainly due to a decrease in breath duration.

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    Figure 6.

    Enhanced dependence of Egr2cre;P2b27Alacki mice on O2 chemosensitivity. A, Representative examples of plethysmographic recordings of P4 mutant and control mice in air and in response to 100% O2. Early and late phases correspond to the first and the second half of the 3 min 100% O2 exposure, respectively. B, Total apnea time in mutants (black circles) and controls (white circles) in air or in response to 100% O2 (shaded area). Each circle represents the mean ± SEM over a 30 s period. C, Mean values of ventilation in air or in response to 100% O2 measured in apnea-free periods (noted as VE). D, Mean values of ventilation in air or in response to 100% O2 averaged over the entire 30 s period, including apneas (VEM). E, ΔVE, ΔTTOT, and ΔVT values expressed as percentage of baseline values in apnea-free periods. F, ΔVEM values when including apnea periods. In 100% O2, the mutants, but not the controls, showed a massive increase in the time spent in apnea. The ventilatory depression caused by 100% O2 was more sustained in the mutants than in the controls in apnea-free periods. This difference was greatly enhanced when the calculation of mean ventilation included apnea periods.

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    Table 1.

    Determination of PCO2 and pH in the blood of P9 Egr2+/+;Phox2b27Alacki/+ (control) and Egr2cre/+;Phox2b27Alacki/+ (mutant) pups

    Control ± SD (n = 15)Mutant ± SD (n = 14)p value
    PCO2 (mmHg)39.8 ± 3.540.0 ± 4.50.895
    pH7.47 ± 0.047.52 ± 0.050.008
    Body weight (g)5.01 ± 0.664.04 ± 0.060.0001
    Body temperature (°C)34.2 ± 0.633.6 ± 0.60.01
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The Journal of Neuroscience: 31 (36)
Journal of Neuroscience
Vol. 31, Issue 36
7 Sep 2011
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Breathing without CO2 Chemosensitivity in Conditional Phox2b Mutants
Nelina Ramanantsoa, Marie-Rose Hirsch, Muriel Thoby-Brisson, Véronique Dubreuil, Julien Bouvier, Pierre-Louis Ruffault, Boris Matrot, Gilles Fortin, Jean-François Brunet, Jorge Gallego, Christo Goridis
Journal of Neuroscience 7 September 2011, 31 (36) 12880-12888; DOI: 10.1523/JNEUROSCI.1721-11.2011

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Breathing without CO2 Chemosensitivity in Conditional Phox2b Mutants
Nelina Ramanantsoa, Marie-Rose Hirsch, Muriel Thoby-Brisson, Véronique Dubreuil, Julien Bouvier, Pierre-Louis Ruffault, Boris Matrot, Gilles Fortin, Jean-François Brunet, Jorge Gallego, Christo Goridis
Journal of Neuroscience 7 September 2011, 31 (36) 12880-12888; DOI: 10.1523/JNEUROSCI.1721-11.2011
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