RESUMO
The effects of a deficiency of glycinergic inhibition deriving from mutations of the glycine-receptor gene Glra1 on the breathing pattern of oscillator mice were studied. We compared the development of breathing frequency, tidal volume and minute ventilation from control mice (wild type- and heterozygous oscillator mice) with those of homozygous oscillator mice during early postnatal periods from p9 until p21. The changes of ventilation were correlated with body-weight and changes in blood-pH. During the second to third weeks of postnatal development, breathing frequency increased from 310 to 445.4 mm-1 in control mice. Oscillator mice reached a maximal value of 313.3 min-1 at p18 followed by a fast decrease to 233.0 min-1. This decrease is caused by a prolongation of expiratory duration. Tidal volume showed a steady increase from 6.6 to 15.1 microliters in control animals. In comparison, oscillator mice showed significant lower values after p14. After p15, minute ventilation of oscillator mice declined as compared with control animals leading to respiratory acidosis at p20.
Assuntos
Relógios Biológicos/genética , Receptores de Glicina/deficiência , Receptores de Glicina/genética , Respiração/genética , Animais , Animais Recém-Nascidos/genética , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Ventilação Pulmonar/genética , Receptores de Glicina/fisiologia , Volume de Ventilação Pulmonar/genéticaRESUMO
The RUNX transcription factors are important regulators of linage-specific gene expression in major developmental pathways. Recently, we demonstrated that Runx3 is highly expressed in developing cranial and dorsal root ganglia (DRGs). Here we report that within the DRGs, Runx3 is specifically expressed in a subset of neurons, the tyrosine kinase receptor C (TrkC) proprioceptive neurons. We show that Runx3-deficient mice develop severe limb ataxia due to disruption of monosynaptic connectivity between intra spinal afferents and motoneurons. We demonstrate that the underlying cause of the defect is a loss of DRG proprioceptive neurons, reflected by a decreased number of TrkC-, parvalbumin- and beta-galactosidase-positive cells. Thus, Runx3 is a neurogenic TrkC neuron-specific transcription factor. In its absence, TrkC neurons in the DRG do not survive long enough to extend their axons toward target cells, resulting in lack of connectivity and ataxia. The data provide new genetic insights into the neurogenesis of DRGs and may help elucidate the molecular mechanisms underlying somatosensory-related ataxia in humans.