MASH-1/RET pathway involvement in development of brain stem control of respiratory frequency in newborn mice

• Published in: Physiological genomics 2001-12, Vol.7 (2), p.149-157
• Main Authors: DAUGER, STEPHANE, GUIMIOT, FABIEN, RENOLLEAU, SYLVAIN, LEVACHER, BEATRICE, BODA, BERNADETTE, MAS, CHRISTOPHE, NEPOTE, VIRGINIE, SIMONNEAU, MICHEL, GAULTIER, CLAUDE, GALLEGO, JORGE
• Format: Article
• Language: English
• Subjects: Adaptation, Physiological; Animals; Animals, Newborn; Basic Helix-Loop-Helix Transcription Factors; Brain Stem - metabolism; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Drosophila Proteins; Heterozygote; Homozygote; In Situ Hybridization; Mice; Mice, Knockout; Nerve Net - physiology; Periodicity; Phenotype; Plethysmography; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-ret; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Respiration; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Signal Transduction - physiology; Time Factors; Transcription Factors - deficiency; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 1094-8341; 1531-2267
• DOI: 10.1152/physiolgenomics.00056.2001

1 Laboratoire de Neurologie et Physiologie du Développement, Institut National de la Santé et de la Recherche Médicale E9935 2 Service de Pédiatrie Réanimation, Hôpital Robert Debré 3 Service de Physiologie, Hôpital Robert Debré, 75019 Paris, France 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. breathing; quantitative reverse transcription-polymerase chain reaction; in situ hybridization; plethysmography