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The Journal of Neuroscience, May 2, 2007, 27(18):4947-4956; doi:10.1523/JNEUROSCI.5299-06.2007

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Cellular/Molecular
Conditional NF-L Transgene Expression in Mice for In Vivo Analysis of Turnover and Transport Rate of Neurofilaments

Stéphanie Millecamps,^1,2 Geneviève Gowing,¹ Olga Corti,³ Jacques Mallet,² and Jean-Pierre Julien¹

¹Centre de Recherche du Centre Hospitalier de l'Université Laval, Department of Anatomy and Physiology of Laval University, Quebec, Canada G1V 4G2, ²Centre National de la Recherche Scientifique Unité Mixte de Recherche 7091, Université Pierre et Marie Curie-Paris 6, Hôpital de la Pitié-Salpêtrière, 75013 Paris, France, and ³Institut National de la Santé et de la Recherche Médicale U679, Hôpital de la Pitié-Salpêtrière, 75651 Paris, Cedex 13, France

Correspondence should be addressed to Jean-Pierre Julien, Research Centre of Centre de Recherche du Centre Hospitalier de l'Université Laval, Department of Anatomy and Physiology, Laval University, 2705 Boulevard Laurier, Quebec, Canada G1V 4G2. Email: jean-pierre.julien{at}crchul.ulaval.ca

We generated mice with doxycycline control of a human neurofilament light (NF-L) transgene in the context of the absence (tTA;hNF-L;NF-L^–/–) or presence (tTA;hNF-L;NF-L^+/–) of endogenous mouse NF-L proteins. Doxycycline treatment caused the rapid disappearance of human NF-L (hNF-L) mRNA in tTA;hNF-L mice, but the hNF-L proteins remained with a half-life of 3 weeks in the brain. In the sciatic nerve, the disappearance of hNF-L proteins after doxycycline treatment occurred in synchrony along the sciatic nerve, suggesting a proteolysis of NF proteins along the entire axon. The presence of permanent NF network in tTA;hNF-L;NF-L^+/– mice further stabilized and extended longevity of hNF-L proteins by several months. Surprisingly, after cessation of doxycycline treatment, there was no evidence of leading front of newly synthesized hNF-L proteins migrating into sciatic nerve axons devoid of NF structures. The hNF-L proteins detected at weekly intervals reappeared and accumulated in synchrony at similar rate along nerve segments, a phenomenon consistent with a fast hNF-L transport into axons. We estimated the hNF-L transport rate to be of 10 mm/d in axons devoid of NF structures based on the use of an adenovirus encoding tet-responsive transcriptional activator to transactivate the hNF-L transgene in hypoglossal motor neurons. These results provide in vivo evidence that the stationary NF network in axons is a key determinant of half-life and transport rate of NF proteins.

Key words: neurofilaments; axonal transport; turnover; doxycycline; transgenic; proteolysis

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Received Dec. 7, 2006; revised March 6, 2007; accepted March 27, 2007.

Correspondence should be addressed to Jean-Pierre Julien, Research Centre of Centre de Recherche du Centre Hospitalier de l'Université Laval, Department of Anatomy and Physiology, Laval University, 2705 Boulevard Laurier, Quebec, Canada G1V 4G2. Email: jean-pierre.julien{at}crchul.ulaval.ca

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