Constitutive expression of p21H-Ras(Val12) in neurons induces increased axonal size and dendritic microtubule density in vivo.
ABSTRACT 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. It is concluded that expression of Val12-Ha-Ras in pyramidal neurons results in remodelling of neocortical structuring which strongly implicates a crucial involvement of Ras in cortical plasticity.International Journal of Developmental Neuroscience 06/2004; 22(3):165-73. DOI:10.1016/j.ijdevneu.2004.02.001 · 2.92 Impact Factor
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ABSTRACT: In the present study we show that overexpression of constitutively active Ras amplifies the dendritic remodeling observed when animals were allowed to be physically active. The monomeric G-protein Ras is a key molecular trigger of distinct signal transduction pathways that play an important role in proper functioning of neurons. Our previous studies on Ras-transgenic synRas mice have demonstrated a considerable impact of Ras on dendritic growth, extension and synaptic connectivity of neurons. Voluntary access to a running wheel resulted in enlargement of hippocampal pyramidal cell dendrites in wild-type mice as expected. However, constitutively elevated Ras activity further enhanced dendritic growth and branching especially of apical arbors. The resultant dendritic surface gain was paralleled by a significant increase in dendritic spine density. Since Ras is crucially involved in signaling and cascades of neurotrophins that are elevated after physical activity, these results strongly suggest an important role of Ras in dendritic dynamics during induced neuronal remodeling.International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 07/2009; 27(4):407-11. DOI:10.1016/j.ijdevneu.2009.03.002 · 2.92 Impact Factor