Abnormal development of the neuromuscular junction in Nedd4-deficient mice

Yun Liu, Ronald W. Oppenheim, Yoshie Sugiura, Weichun Lin

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)153-166
Number of pages14
JournalDevelopmental Biology
Volume330
Issue number1
DOIs
StatePublished - Jun 1 2009

Fingerprint

Neuromuscular Junction
Motor Neurons
Muscles
Ubiquitin-Protein Ligases
Schwann Cells
Skeletal Muscle Fibers
Presynaptic Terminals
Synapses
Muscle Cells
Nervous System
Axons
Appointments and Schedules
Skeletal Muscle
Embryonic Structures
Yeasts
Parturition
Mutation
Membranes
Genes

Keywords

  • Mammalian development
  • Motoneuron
  • Mouse genetics
  • Neuromuscular junction
  • Synaptogenesis

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology
  • Molecular Biology

Cite this

Abnormal development of the neuromuscular junction in Nedd4-deficient mice. / Liu, Yun; Oppenheim, Ronald W.; Sugiura, Yoshie; Lin, Weichun.

In: Developmental Biology, Vol. 330, No. 1, 01.06.2009, p. 153-166.

Research output: Contribution to journalArticle

Liu, Yun ; Oppenheim, Ronald W. ; Sugiura, Yoshie ; Lin, Weichun. / Abnormal development of the neuromuscular junction in Nedd4-deficient mice. In: Developmental Biology. 2009 ; Vol. 330, No. 1. pp. 153-166.
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