TY - JOUR
T1 - Abnormal development of the neuromuscular junction in Nedd4-deficient mice
AU - Liu, Yun
AU - Oppenheim, Ronald W.
AU - Sugiura, Yoshie
AU - Lin, Weichun
N1 - Funding Information:
We would like to thank Laurie Mueller and David Prevette for their excellent technical assistance, and Drs. Natalie Kim and Steven Burden for their valuable suggestions on single muscle fiber preparation. We are indebted to Drs. Thomas Südhof, Jane Johnson, Keith Wharton, Kim Huber, Ege Kavalali and Jonathan Terman for their critical comments on the manuscript. This work was supported by grants (to W. Lin) from NIH/NINDS (NS055028), the Edward Mallinckrodt, Jr. Scholar Program and the Cain Foundation in Medical Research, and NIH/NINDS grant NS53527 (R. W. Oppenheim).
PY - 2009/6/1
Y1 - 2009/6/1
N2 - Nedd4 (neural precursor cell expressed developmentally down-regulated gene 4) is an E3 ubiquitin ligase highly conserved from yeast to humans. The expression of Nedd4 is developmentally down-regulated in the mammalian nervous system, but the role of Nedd4 in mammalian neural development remains poorly understood. Here we show that a null mutation of Nedd4 in mice leads to perinatal lethality: mutant mice were stillborn and many of them died in utero before birth (between E15.5-E18.5). In Nedd4 mutant embryos, skeletal muscle fiber sizes and motoneuron numbers are significantly reduced. Surviving motoneurons project axons to their target muscles on schedule, but motor nerves defasciculate upon reaching the muscle surface, suggesting that Nedd4 plays a critical role in fine-tuning the interaction between the nerve and the muscle. Electrophysiological analyses of the neuromuscular junction (NMJ) demonstrate an increased spontaneous miniature endplate potential (mEPP) frequency in Nedd4 mutants. However, the mutant neuromuscular synapses are less responsive to membrane depolarization, compared to the wildtypes. Ultrastructural analyses further reveal that the pre-synaptic nerve terminal branches at the NMJs of Nedd4 mutants are increased in number, but decreased in diameter compared to the wildtypes. These ultrastructural changes are consistent with functional alternation of the NMJs in Nedd4 mutants. Unexpectedly, Nedd4 is not expressed in motoneurons, but is highly expressed in skeletal muscles and Schwann cells. Together, these results demonstrate that Nedd4 is involved in regulating the formation and function of the NMJs through non-cell autonomous mechanisms.
AB - Nedd4 (neural precursor cell expressed developmentally down-regulated gene 4) is an E3 ubiquitin ligase highly conserved from yeast to humans. The expression of Nedd4 is developmentally down-regulated in the mammalian nervous system, but the role of Nedd4 in mammalian neural development remains poorly understood. Here we show that a null mutation of Nedd4 in mice leads to perinatal lethality: mutant mice were stillborn and many of them died in utero before birth (between E15.5-E18.5). In Nedd4 mutant embryos, skeletal muscle fiber sizes and motoneuron numbers are significantly reduced. Surviving motoneurons project axons to their target muscles on schedule, but motor nerves defasciculate upon reaching the muscle surface, suggesting that Nedd4 plays a critical role in fine-tuning the interaction between the nerve and the muscle. Electrophysiological analyses of the neuromuscular junction (NMJ) demonstrate an increased spontaneous miniature endplate potential (mEPP) frequency in Nedd4 mutants. However, the mutant neuromuscular synapses are less responsive to membrane depolarization, compared to the wildtypes. Ultrastructural analyses further reveal that the pre-synaptic nerve terminal branches at the NMJs of Nedd4 mutants are increased in number, but decreased in diameter compared to the wildtypes. These ultrastructural changes are consistent with functional alternation of the NMJs in Nedd4 mutants. Unexpectedly, Nedd4 is not expressed in motoneurons, but is highly expressed in skeletal muscles and Schwann cells. Together, these results demonstrate that Nedd4 is involved in regulating the formation and function of the NMJs through non-cell autonomous mechanisms.
KW - Mammalian development
KW - Motoneuron
KW - Mouse genetics
KW - Neuromuscular junction
KW - Synaptogenesis
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U2 - 10.1016/j.ydbio.2009.03.023
DO - 10.1016/j.ydbio.2009.03.023
M3 - Article
C2 - 19345204
AN - SCOPUS:67349270258
SN - 0012-1606
VL - 330
SP - 153
EP - 166
JO - Developmental Biology
JF - Developmental Biology
IS - 1
ER -