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© The Rockefeller University Press, 0021-9525/2000//1537 $5.00
The Journal of Cell Biology, Volume 151, Number 7, , 2000 1537-1548

Transgenic Activation of Ras in Neurons Promotes Hypertrophy and Protects from Lesion-Induced Degeneration

^a Ruhr-University of Bochum, Molecular Neurobiochemistry
^b Developmental Neurobiology, D-44780 Bochum, Germany
^c Novartis, CH-4002 Basel, Switzerland
^d Research Institute of Molecular Pathology (IMP), A-1030 Vienna, Austria
^e Paul-Flechsig-Instititute for Brain Research, D-04109 Leipzig, Germany
^f University of Bonn, Institute of Animal Breeding Science, D-53115 Bonn, Germany
Ruhr-University of Bochum, Molecular Neurobiochemistry, NC/7-174, 44870 Bochum, Germany.49-23-43-21-41-0549-23-43-22-42-30

rolf.heumann{at}ruhr-uni-bochum.de

Ras is a universal eukaryotic intracellular protein integrating extracellular signals from multiple receptor types. To investigate its role in the adult central nervous system, constitutively activated V12-Ha-Ras was expressed selectively in neurons of transgenic mice via a synapsin promoter. Ras-transgene protein expression increased postnatally, reaching a four- to fivefold elevation at day 40 and persisting at this level, thereafter. Neuronal Ras was constitutively active and a corresponding activating phosphorylation of mitogen-activated kinase was observed, but there were no changes in the activity of phosphoinositide 3-kinase, the phosphorylation of its target kinase Akt/PKB, or expression of the anti-apoptotic proteins Bcl-2 or Bcl-X_L. Neuronal Ras activation did not alter the total number of neurons, but induced cell soma hypertrophy, which resulted in a 14.5% increase of total brain volume. Choline acetyltransferase and tyrosine hydroxylase activities were increased, as well as neuropeptide Y expression. Degeneration of motorneurons was completely prevented after facial nerve lesion in Ras-transgenic mice. Furthermore, neurotoxin-induced degeneration of dopaminergic substantia nigra neurons and their striatal projections was greatly attenuated. Thus, the Ras signaling pathway mimics neurotrophic effects and triggers neuroprotective mechanisms in adult mice. Neuronal Ras activation might become a tool to stabilize donor neurons for neural transplantation and to protect neuronal populations in neurodegenerative diseases.

Key Words: Ras • neuron • transgenic • protection • mouse

© 2000 The Rockefeller University Press

H. Berns' present address is University of Basel, Department of Clinical-Biological Sciences (DKBW) and Research, Hebelstr. 20, CH-4031 Basel, Switzerland.

Abbreviations used in this paper: Chat, choline acetyltransferase; ERK, extracellular signal–regulated kinase; GAD, glutamic acid decarboxylase; GAP, GTPase activating protein; IRES, internal ribosomal entry site; lacZ, β-galactosidase; MAPK, mitogen-activated protein kinase; MPP⁺, 1-methyl-4-phenylpyridinium; MPTP, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NF, neurofibromin; NMR, nuclear magnetic resonance; NPY, neuropeptide Y; P, postnatal; PI 3-kinase, phosphoinositide 3-kinase; PKB, phosphoinositide-dependent protein kinase; TG, transgene; TH, tyrosine hydroxylase; wt, wild-type; 6-OHDA, 6-hydroxydopamine.

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