Altered neuronal responses and regulation of neurotrophic proteins in the medial septum following fimbria-fornix transection in CNTF- and leukaemia inhibitory factor-deficient mice.
Degeneration of axotomized GABAergic septohippocampal neurones has been shown to be enhanced in ciliary neurotrophic factor (CNTF)-deficient mice following fimbria-fornix transection (FFT), indicating a neuroprotective function of endogenous CNTF. Paradoxically, however, the cholinergic population of septohippocampal neurones was more resistant to axotomy in these mutants. As leukaemia inhibitory factor (LIF) has been identified as a potential neuroprotective factor for the cholinergic medial septum (MS) neurones, FFT-induced responses were compared in CNTF(-/-), LIF(-/-) and CNTF/LIF double knockout mice. In CNTF(-/-) mice, FFT-induced cholinergic degeneration was confirmed to be attenuated as compared with wildtype mice. The expression of both LIF and LIF receptor beta was increased in the MS providing a possible explanation for the enhanced neuronal resistance to FFT in these animals. However, ablation of the LIF gene also produced paradoxical effects; following FFT in LIF(-/-) mice no loss of GABAergic or cholinergic MS neurones was detectable during the first postlesional week, suggesting that other efficient neuroprotective mechanisms are activated in these animals. In fact, enhanced activation of astrocytes, a source of neurotrophic proteins, was indicated by increased up-regulation of glial fibrillary acidic protein and vimentin expression. In addition, mRNA levels for neurotrophin signalling components (e.g. nerve growth factor, p75(NTR)) were differentially regulated. The positive effect on axotomized cholinergic neurones seen in CNTF(-/-) and LIF(-/-) mice as well as the increased up-regulation of astrogliose markers was abolished in CNTF/LIF double knockout animals. Our results indicate that endogenous CNTF and LIF are involved in the regulation of neuronal survival following central nervous system lesion and are integrated into a network of neurotrophic signals that mutually influence their expression and function.
Naumann
Thomas
T
Institute of Anatomy and Cell Biology, Center of Neuroscience, Albertstrasse 21, D-79104 Freiburg, Germany.
Steup
Andreas
A
Schnell
Oliver
O
Schubert
Klaus Oliver
KO
Zhi
Qixia
Q
Guijarro
Christian
C
Kirsch
Matthias
M
Hofmann
Hans-Dieter
HD
D000818:Animals; D019771:Axotomy; D002452:Cell Count; D020934:Ciliary Neurotrophic Factor / Q000172:deficiency* / Q000235:genetics*; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D020712:Fornix, Brain / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry; D053605:Leukemia Inhibitory Factor / Q000172:deficiency* / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000473:pathology; D009414:Nerve Growth Factors / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D010275:Parasympathetic Nervous System / Q000166:cytology / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020665:Septum of Brain / Q000166:cytology* / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D020934:Ciliary Neurotrophic Factor; D016207:Cytokines; D053605:Leukemia Inhibitory Factor; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D005680:gamma-Aminobutyric Acid