Ciliary neurotrophic factor recruitment of glucagon-like peptide-1 mediates neurogenesis, allowing immortalization of adult murine hypothalamic neurons.
The distinct lack of cell lines derived from the adult brain is evident. Ciliary neurotrophic factor (CNTF) triggers neurogenesis in primary culture from adult mouse hypothalamus, as detected by bromodeoxyuridine and Ki67 immunostaining. Using SV-40 T-antigen, we immortalized dividing neurons and generated clonal cell lines expressing neuropeptides and receptors involved in neuroendocrine function. We hypothesized that proglucagon-derived peptides may be the mechanistic downstream effectors of CNTF due to documented neuroprotective and proliferative effects. Indeed, proglucagon gene expression was induced by CNTF, and exposure of primary cells to glucagon-like peptide-1 receptor (GLP-1) agonist, exendin-4, induced cell proliferation. Intracerebroventricular injection of CNTF into adult mice caused increased expression of proglucagon peptide in the hypothalamus. Using a specific GLP-1-receptor antagonist, we found that neurogenesis was significantly attenuated and primary culture from GLP-1-receptor-knockout mice lacked CNTF-mediated neuronal proliferation, thus linking the induction of neurogenesis in the hypothalamus to GLP-1-receptor signaling.
Belsham
Denise D
DD
Department of Physiology, University of Toronto, Medical Sciences Bldg. 3247A, 1 King's College Cir., Toronto, ON M5S1A8, Canada. d.belsham@utoronto.ca
Fick
Laura J
LJ
Dalvi
Prasad S
PS
Centeno
Maria-Luisa
ML
Chalmers
Jennifer A
JA
Lee
Paul K P
PK
Wang
Yangyang
Y
Drucker
Daniel J
DJ
Koletar
Margaret M
MM
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology*; D005786:Gene Expression Regulation; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D007031:Hypothalamus / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D052336:Proglucagon / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D020934:Ciliary Neurotrophic Factor; D052336:Proglucagon; D052216:Glucagon-Like Peptide 1