Defective respiratory rhythmogenesis and loss of central chemosensitivity in Phox2b mutants targeting retrotrapezoid nucleus neurons.
The retrotrapezoid nucleus (RTN) is a group of neurons in the rostral medulla, defined here as Phox2b-, Vglut2-, neurokinin1 receptor-, and Atoh1-expressing cells in the parafacial region, which have been proposed to function both as generators of respiratory rhythm and as central respiratory chemoreceptors. The present study was undertaken to assess these two putative functions using genetic tools. We generated two conditional Phox2b mutations, which target different subsets of Phox2b-expressing cells, but have in common a massive depletion of RTN neurons. In both conditional mutants as well as in the previously described Phox2b(27Ala) mutants, in which the RTN is also compromised, the respiratory-like rhythmic activity normally seen in the parafacial region of fetal brainstem preparations was completely abrogated. Rhythmic motor bursts were recorded from the phrenic nerve roots in the mutants, but their frequency was markedly reduced. Both the rhythmic activity in the RTN region and the phrenic nerve discharges responded to a low pH challenge in control, but not in the mutant embryos. Together, our results provide genetic evidence for the essential role of the Phox2b-expressing RTN neurons both in establishing a normal respiratory rhythm before birth and in providing chemosensory drive.
Dubreuil
Véronique
V
Département de Biologie, Ecole normale supérieure, 75005 Paris, France.
Thoby-Brisson
Muriel
M
Rallu
Murielle
M
Persson
Karin
K
Pattyn
Alexandre
A
Birchmeier
Carmen
C
Brunet
Jean-François
JF
Fortin
Gilles
G
Goridis
Christo
C
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002628:Chemoreceptor Cells / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009415:Nerve Net / Q000196:embryology / Q000378:metabolism / Q000503:physiopathology; D009924:Organ Culture Techniques; D010791:Phrenic Nerve / Q000502:physiology; D012119:Respiration; D012125:Respiratory Center / Q000196:embryology / Q000378:metabolism* / Q000503:physiopathology; D012249:Rhombencephalon / Q000196:embryology / Q000378:metabolism* / Q000503:physiopathology; D014157:Transcription Factors / Q000235:genetics*
D018398:Homeodomain Proteins; C109220:NBPhox protein; D014157:Transcription Factors