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

To directly compare biological activities of the neurotrophins NT4 and BDNF in vivo, we replaced the BDNF coding sequence with the NT4 sequence in mic e (Bdnf(nt4-ki)). Mice expressing NT4 in place of BDNF were viable, in cont rast with BDNF null mutants, which die shortly after birth. Although the Bd nf(nt4-ki/nt4-ki) and wild-type Bdnf(+/+) alleles yielded similar levels of NT4 and BDNF proteins, NT4 supported more sensory neurons than BDNF and pr omoted functional synapse formation in cultured hippocampal neurons. Homozy gous Bdnf(nt4-ki/nt4-ki) mice showed reduced body weight, infertility and s kin lesions, suggesting unique biological activities of NT4 in vivo. The di stinct activities of NT4 and BDNF may result partly from differential activ ation of the TrkB receptor and its down-stream signals.