Abnormal development of the neuromuscular junction in Nedd4-deficient mice

摘要: Nedd4 (neural precursor cell expressed developmentally down-regulated gene 4) is an E3 ubiquitin ligase highly conserved from yeast to humans. The expression of in the mammalian nervous system, but role neural development remains poorly understood. Here we show that a null mutation mice leads perinatal lethality: mutant were stillborn and many them died utero before birth (between E15.5-E18.5). In embryos, skeletal muscle fiber sizes motoneuron numbers are significantly reduced. Surviving motoneurons project axons their target muscles on schedule, motor nerves defasciculate upon reaching surface, suggesting plays critical fine-tuning interaction between nerve muscle. Electrophysiological analyses neuromuscular junction (NMJ) demonstrate increased spontaneous miniature endplate potential (mEPP) frequency mutants. However, synapses less responsive membrane depolarization, compared wildtypes. Ultrastructural further reveal pre-synaptic terminal branches at NMJs mutants number, decreased diameter These ultrastructural changes consistent with functional alternation Unexpectedly, not motoneurons, Schwann cells. Together, these results involved regulating formation function through non-cell autonomous mechanisms.