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Knocking the NT4 gene into the BDNF locus rescues BDNF deficient mice and reveals distinct NT4 and BDNF activities

Abstract

To directly compare biological activities of the neurotrophins NT4 and BDNF in vivo, we replaced the BDNF coding sequence with the NT4 sequence in mice (Bdnfnt4-ki). Mice expressing NT4 in place of BDNF were viable, in contrast with BDNF null mutants, which die shortly after birth. Although the Bdnfnt4-ki/nt4-ki and wild-type Bdnf+/+ alleles yielded similar levels of NT4 and BDNF proteins, NT4 supported more sensory neurons than BDNF and promoted functional synapse formation in cultured hippocampal neurons. Homozygous Bdnfnt4-ki/nt4-ki mice showed reduced body weight, infertility and skin lesions, suggesting unique biological activities of NT4 in vivo. The distinct activities of NT4 and BDNF may result partly from differential activation of the TrkB receptor and its down-stream signals.

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Figure 1: Replacement of the BDNF coding sequence with NT4 codons through the Cre-loxP system.
Figure 2: Rescue of vestibular neurons in Bdnfnt4-ki/nt4-ki newborn mice.
Figure 3: Knock-in NT4 promotes functional synapse formation in cultured hippocampal neurons.
Figure 4: NT4 is a more potent activator of the c-fos promoter than BDNF in mouse cortical cultures.

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Acknowledgements

We would like to thank Brian Bates, Jeffrey Cottrell, Scott Waddell and Michael Greenberg for reading the manuscript. We appreciate the technical support from Jesse Dausemann, Ruth Curry and Jeanne Reis. This work was supported by NIH grants (R.J. and G.L.), Deutsche Forschungsgemeinschaft and the European Union (R.K.), a Medical Foundation Postdoctoral Fellowship (G.F.), and RIKEN-MIT fellowships (C.E. and J.J.R.).

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Correspondence to Rudolf Jaenisch.

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Fan, G., Egles, C., Sun, Y. et al. Knocking the NT4 gene into the BDNF locus rescues BDNF deficient mice and reveals distinct NT4 and BDNF activities. Nat Neurosci 3, 350–357 (2000). https://doi.org/10.1038/73921

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