Constitutive Expression of p21H-RasVal12 in Neurons Induces Increased Axonal Size and Dendritic Microtubule Density in Vivo
The small G protein p21Ras is a key signal transducer mediating cellular growth and proliferation responses to extracellular stimuli. We investigated by electron microscopy the effects of augmented p21Ras activity on neuronal processes and microtubule arrangement in vivo. We used transgenic mice with a neuron-specific overexpression of p21H-RasVal12, which starts postnatally around Day 15. Axonal and dendritic diameters and the numerical density of dendritic microtubules were analyzed at postnatal Day 12 before the onset of transgene expression and in adult mice. In adult transgenic mice, calibers of both axons (corpus callosum) and dendrites (layers II/III of somatosensory cortex) were enlarged by about 57% and 79%, respectively. The increase in dendritic calibers was associated with an increment in the amount of microtubules. Even in dendrites of equivalent diameters, the number of microtubules was higher in transgenic mice compared to that in wild-type mice suggesting an elevated microtubule density. Changes in process diameters or microtubule density were not observed at postnatal Day 12 before relevant transcription of transgenic p21H-RasVal12. The present results extend previous findings on neuronal hypertrophy as a consequence of p21H-RasVal12 expression and suggest a profound influence on the dendritic microtubule network.
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ABSTRACT: Es wird heutzutage als hinreichend anerkannt, dass während der gesamten Lebensspanne Neurone in zwei neurogenen Gehirnregionen entstehen, in den ventrikulären Wänden und im Gyrus dentatus der Hippocampus. Die transgene synRas Maus, welche konstitutiv aktiviertes Ha-Ras wahlweise in ausgereiften Neuronen exprimiert, zeigt eine reduzierte hippokampale Proliferation. Genetische und epigenetische Faktoren können die adulte Neurogenese beeinflussen. Dennoch ist sehr wenig über die Mechanismen, die diesen Regulationen zugrunde liegen bekannt. In meiner Dissertation lege ich den Schwerpunkt auf die Tatsache, dass diese Regulationen arts-, alters- und kontext-abhängig sind. Die funktionelle Relevanz dieser neu generierten Neurone ist noch unklar. Jedoch wurden inzwischen Beweise erbracht, die auf die Wichtigkeit dieser Neurone im Lernvorgang und in der Gedächtnisbildung hindeuten, und dass die reduzierte Proliferation für das Entstehen von Depression verantwortlich sein könnte.
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ABSTRACT: Neurotrophic actions are critically controlled and transmitted to cellular responses by the small G protein Ras which is therefore essential for normal functioning and plasticity of the nervous system. The present study summarises findings of recent studies on morphological changes in the neocortex of synRas mice expressing Val12-Ha-Ras in vivo under the control of the rat synapsin I promoter. In the here reported model (introduced by Heumann et al. [J. Cell Biol. 151 (2000) 1537]), transgenic Val12-Ha-Ras expression is confined to the pyramidal cell population and starts postnatally at a time, when neurons are postmitotic and their developmental maturation has been basically completed. Expression of Val12-Ha-Ras results in a significant enlargement of pyramidal neurons. Size, complexity and spine density of dendritic trees are increased, which leads, finally, to cortical expansion. However, the main morphological design principles of ‘transgenic’ pyramidal cells remain preserved. In addition to somato-dendritic changes, expression of Val12-Ha-Ras in pyramidal cells induces augmented axon calibres and upregulates the establishment of efferent boutons. Despite the enlargement of cortical size, the overall density of terminals representing intra- or interhemispheric, specific and non-specific afferents is unchanged or even higher in transgenic mice suggesting a significant increase in the total afferent input to the neocortex. Although interneurons do not express the transgene and are therefore excluded from direct, intrinsic Val12-Ha-Ras effects, they respond with morphological adaptations to structural changes. Thus, dendritic arbours of interneurons are extended to follow the cortical expansion and basket cells establish a denser inhibitory innervation of ‘transgenic’ pyramidal cells perikarya.
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ABSTRACT: The small G protein Ras, which is involved critically in neurotrophic signal transduction, has been implicated in neuronal plasticity of both the developing and the adult nervous systems. In the present study, the cumulative effects of constitutive Ras activity from early in postnatal development into the adult upon the morphology of hippocampal pyramidal neurons were investigated in synRas mice overexpressing Val12-Ha-Ras postmitotically under the control of the rat synapsin I promoter. In synRas mice, stereologic investigations revealed hypertrophy of the hippocampus associated with an increase in perikaryal size of pyramidal neurons within the CA2/CA3 region and the gyrus dentatus. Morphometric analyses of Lucifer Yellow-filled CA1 pyramidal neurons, in addition, demonstrated considerable expansion of dendritic arbors. The increase in basal dendritic size was caused primarily by alterations of intermediate and distal segments and was associated with an enlarged dendritic surface. Apical dendrites showed similar but more moderate changes, which were attributed mainly to elongation of terminal segments. Sholl analyses illustrated higher complexity of both basal and apical trees. Despite significant morphologic alterations, dendritic arbors preserve their major design principles. The synaptic density within the stratum radiatum of CA1 remained unchanged; however, increases in the total hippocampal volume and in apical dendritic size imply an increment in the absolute number of synaptic contacts. The data presented here suggest a critical involvement of Ras dependent signaling in morphoregulatory processes during the maturation and in the maintenance of hippocampal pyramidal neurons.
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