Ret deficiency in mice impairs the development of A5 and A6 neurons and the functional maturation of the respiratory rhythm

Autor: Michel Simonneau, Henri Burnet, Michelle Bévengut, Jean-Marc Pequignot, G. Maussion, Vassilis Pachnis, Jean-Charles Viemari, V. Népote, Gérard Hilaire
Přispěvatelé: Groupe d'étude des réseaux moteurs - GERM (GERMG), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Développement du neocortex, environnement foetal et conséquences fonctionnelles postnatales, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie intégrative, cellulaire et moléculaire (PICM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Division of Molecular Neurobiology, National Institute for Medical Research, Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiologie des Régulations Energétiques, Cellulaires et Moléculaires, Neurobiologie génétique et intégrative (NGI), Centre National de la Recherche Scientifique (CNRS), Institut de Neurobiologie Alfred Fessard (INAF)
Jazyk: angličtina
Rok vydání: 2005
Předmět:
endocrine system diseases
Respiratory System
MESH: Neurons
MESH: Mice
Knockout
Network Activity
MESH: Genotype
Mice
Norepinephrine
0302 clinical medicine
MESH: Pregnancy
MESH: Biogenic Monoamines
Pregnancy
Pons
MESH: Animals
Respiratory system
In Situ Hybridization
MESH: Respiratory System
Mice
Knockout
Neurons
0303 health sciences
General Neuroscience
MESH: Rhombencephalon
Immunohistochemistry
MESH: Respiratory Mechanics
Female
Brainstem
medicine.symptom
CatecholaminergicSystemFetal
medicine.medical_specialty
endocrine system
[SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT]
Genotype
In situ hybridization
Biology
MESH: Proto-Oncogene Proteins c-ret
03 medical and health sciences
MESH: In Situ Hybridization
MESH: Mice
Inbred C57BL
Internal medicine
MESH: Norepinephrine
MESH: Homeodomain Proteins
medicine
Animals
Biogenic Monoamines
RNA
Messenger
[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biochemistry [q-bio.BM]
MESH: Mice
Medulla
030304 developmental biology
MESH: RNA
Messenger
Homeodomain Proteins
Fetus
Tyrosine hydroxylase
Proto-Oncogene Proteins c-ret
MESH: Pons
MESH: Immunohistochemistry
Hypoxia (medical)
Mice
Inbred C57BL
Rhombencephalon
Endocrinology
MESH: Nerve Net
MESH: Brain Stem
Respiratory Mechanics
Nerve Net
MESH: Female
030217 neurology & neurosurgery
Brain Stem
Zdroj: European Journal of Neuroscience
European Journal of Neuroscience, 2005, 22, pp.2403-2412. ⟨10.1111/j.1460-9568.2005.04441.x⟩
European Journal of Neuroscience, Wiley, 2005, 22, pp.2403-2412. ⟨10.1111/j.1460-9568.2005.04441.x⟩
European Journal of Neuroscience, Wiley, 2005, 22 (10), pp.2403-12. ⟨10.1111/j.1460-9568.2005.04441.x⟩
European Journal of Neuroscience, 2005, 22 (10), pp.2403-12. ⟨10.1111/j.1460-9568.2005.04441.x⟩
ISSN: 0953-816X
1460-9568
DOI: 10.1111/j.1460-9568.2005.04441.x⟩
Popis: Although a normal respiratory rhythm is vital at birth, little is known about the genetic factors controlling Although a normal respiratory rhythm is vital at birth, little is known about the genetic factors controlling the prenatal maturation of the respiratory network in mammals. In Phox2a mutant mice, which do not express A6 neurons, we previously hypothesized that the release of endogenous norepinephrine by A6 neurons is required for a normal respiratory rhythm to occur at birth. Here we investigated the role of the Ret gene, which encodes a transmembrane tyrosine kinase receptor, in the maturation of norepinephrine and respiratory systems. As Ret-null mutants (Ret-/-) did not survive after birth, our experiments were performed in wild-type (wt) and Ret-/- fetuses exteriorized from pregnant heterozygous mice at gestational day 18. First, in wt fetuses, quantitative in situ hybridization revealed high levels of Ret transcripts in the pontine A5 and A6 areas. Second, in Ret-/- fetuses, high-pressure liquid chromatography showed significantly reduced norepinephrine contents in the pons but not the medulla. Third, tyrosine hydroxylase immunocytochemistry revealed a significantly reduced number of pontine A5 and A6 neurons but not medullary norepinephrine neurons in Ret-/- fetuses. Finally, electrophysiological and pharmacological experiments performed on brainstem 'en bloc' preparations demonstrated impaired resting respiratory activity and abnormal responses to central hypoxia and norepinephrine application in Ret-/- fetuses. To conclude, our results show that Ret gene contributes to the prenatal maturation of A6 and A5 neurons and respiratory system. They support the hypothesis that the normal maturation of the respiratory network requires afferent activity corresponding to the A6 excitatory and A5 inhibitory input balance.
Databáze: OpenAIRE
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