MASH-1/RET pathway involvement in development of brain stem control of respiratory frequency in newborn mice.
Respiratory abnormalities have been described in MASH-1 (mammalian achaete-scute homologous gene) and c-RET ("rearranged during transfection") mutant newborn mice. However, the neural mechanisms underlying these abnormalities have not been studied. We tested the hypothesis that the MASH-1 mutation may impair c-RET expression in brain stem neurons involved in the control of breathing. To do this, we analyzed brain stem c-RET expression and respiratory phenotype in MASH-1 +/+ wild-type, MASH-1 +/- heterozygous, and MASH-1 -/- knock-out newborn mice during the first 2 h of life. In MASH-1 -/- newborns, c-RET gene expression was absent in the noradrenergic nuclei (A2, A5, A6, A7) that contribute to modulate respiratory frequency and in scattered cells of the rostral ventrolateral medulla. The c-RET transcript levels measured by quantitative RT-PCR were lower in MASH-1 -/- and MASH-1 +/- than in MASH-1 +/+ brain stems (P = 0.001 and P = 0.003, respectively). Breath durations were shorter in MASH-1 -/- and MASH-1 +/- than in MASH-1 +/+ mice (P = 0.022) and were weakly correlated with c-RET transcript levels (P = 0.032). Taken together, these results provide evidence that MASH-1 is upstream of c-RET in noradrenergic brain stem neurons important for respiratory rhythm modulation.
Dauger
S
S
Laboratoire de Neurologie et Physiologie du Développement, Institut National de la Santé et de la Recherche Médicale E9935, Service de Pédiatrie Réanimation, Hôpital Robert Debré, Service de Physiologie, Hôpital Robert Debré, 75019 Paris, France.
Guimiot
F
F
Renolleau
S
S
Levacher
B
B
Boda
B
B
Mas
C
C
Nepote
V
V
Simonneau
M
M
Gaultier
C
C
Gallego
J
J
D000222:Adaptation, Physiological; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins; D001933:Brain Stem / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins; D006579:Heterozygote; D006720:Homozygote; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D009415:Nerve Net / Q000502:physiology; D010507:Periodicity; D010641:Phenotype; D010991:Plethysmography; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012119:Respiration; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D012333:RNA, Messenger; D020794:Receptor Protein-Tyrosine Kinases; D014157:Transcription Factors; C499317:Ascl1 protein, mouse; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse