Aberrant development of motor axons and neuromuscular synapses in erbB2-deficient mice

Lin, Weichun; Sanchez, Hugo B.; Deerinck, Tom; Morris, Jacqueline K.; Ellisman, Mark H.; Lee, Kuo Fen

doi:10.1073/pnas.97.3.1299

Cited by 168 publications

(123 citation statements)

References 35 publications

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“…This is the stage at which the developing phrenic nerve first arrives at the diaphragm muscle and is before the clustering of muscle AChRs (Lupa and Hall, 1989;Lin et al, 2000). Our results showed that motor nerves exit the spinal cord normally and remain fasciculated en route to their muscle target in the Chat mutant embryos (data not shown).…”

Section: Increased Innervation and Spinal Motor Neuron Survivalsupporting

confidence: 48%

Aberrant Patterning of Neuromuscular Synapses in Choline Acetyltransferase-Deficient Mice

et al. 2003

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In this study we examined the developmental roles of acetylcholine (ACh) by establishing and analyzing mice lacking choline acetyltransferase (ChAT), the biosynthetic enzyme for ACh. As predicted, ChAT-deficient embryos lack both spontaneous and nerve-evoked postsynaptic potentials in muscle and die at birth. In mutant embryos, abnormally increased nerve branching occurs on contact with muscle, and hyperinnervation continues throughout subsequent prenatal development. Postsynaptically, ACh receptor clusters are markedly increased in number and occupy a broader muscle territory in the mutants. Concomitantly, the mutants have significantly more motor neurons than normal. At an ultrastructural level, nerve terminals are smaller in mutant neuromuscular junctions, and they make fewer synaptic contacts to the postsynaptic muscle membrane, although all of the typical synaptic components are present in the mutant. These results indicate that ChAT is uniquely essential for the patterning and formation of mammalian neuromuscular synapses.

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Section: Increased Innervation and Spinal Motor Neuron Survivalsupporting

confidence: 48%

Aberrant Patterning of Neuromuscular Synapses in Choline Acetyltransferase-Deficient Mice

et al. 2003

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“…In addition, mice deficient in ErbB2 show defects in cranial sensory ganglia likely due to defects in cranial neural crest [119,123]. ErbB2 plays a role in the terminal differentiation of oligodendrocyte precursors to mature oligodendrocytes in the spinal cord [124] as well as in the myelination of peripheral nerves by Schwann cells [125][126][127]. Rescue of the embryonic lethal cardiac defects of ErbB2-deficient mice by myocardium-restricted expression of wild-type ErbB2 results in mice with severe defects in Schwann cell migration in the peripheral nervous system with loss of sensory and motor neurons [125,126].…”

Section: Erbb Members In Mammalian Developmentmentioning

confidence: 99%

“…Neuregulin-1 is expressed in the endocardium and appears to act in a paracrine fashion through myocardium-restricted ErbB2 and ErbB4 to stimulate myocardial trabeculae formation [129,137]. Neuregulin-1-deficient mice also have deficient Schwann cell and cranial ganglia formation similar to those seen in ErbB2 and ErbB3 mutant mice [120,[125][126][127][128]137]. Similarly, deletion of HB-EGF, a ligand for both EGFR and ErbB4, leads to dilated cardiomyopathy similar to conditional mutant mice lacking ErbB2 or ErbB4 in the ventricular myocardium [138].…”

Section: Erbb Members In Mammalian Developmentmentioning

confidence: 99%

The epidermal growth factor receptor family: Biology driving targeted therapeutics

Wieduwilt

Moasser

2008

Cell. Mol. Life Sci.

644

503

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The epidermal growth factor family of receptor tyrosine kinases (ErbBs) plays essential roles in regulating cell proliferation, survival, differentiation and migration. The ErbB receptors carry out both redundant and restricted functions in mammalian development and in the maintenance of tissues in the adult mammal. Loss of regulation of the ErbB receptors underlies many human diseases, most notably cancer. Our understanding of the function and complex regulation of these receptors has fueled the development of targeted therapeutic agents for human malignancies in the last 15 years. Here we review the biology of ErbB receptors, including their structure, signaling, regulation, and roles in development and disease, then briefly touch on their increasing roles as targets for cancer therapy.

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“…NRG binds to ErbB receptors and, through the initiation of Erk signaling pathway, induces the transcription of synapse-specific genes, such as AChR subunits (13). Nonetheless, recent studies indicate that, although conditional mutant mice lacking NRG or ErbB receptors exhibit neuromuscular defects, the pattern of AChR transcription remains grossly normal in these mice (14)(15)(16).…”

mentioning

confidence: 99%

Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclin-dependent kinase 5 null mice

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Cyclin-dependent kinase (Cdk)5 is a key regulator of neural development. We have previously demonstrated that Cdk5͞p35 are localized to the postsynaptic muscle and are implicated in the regulation of neuregulin͞ErbB signaling in myotube culture. To further elucidate whether Cdk5 activity contributes to neuromuscular junction (NMJ) development in vivo, the NMJ of Cdk5 ؊/؊ mice was examined. Consistent with our previous demonstration that Cdk5 phosphorylates ErbB2͞3 to regulate its tyrosine phosphorylation, we report here that the phosphorylation of ErbB2 and ErbB3 and the ErbB2 kinase activity are reduced in Cdk5-deficient muscle. In addition, Cdk5 ؊/؊ mice also display morphological abnormalities at the NMJ pre-and postsynaptically. Whereas the outgrowth of the main nerve trunk is grossly normal, the intramuscular nerve projections exhibit profuse and anomalous branching patterns in the Cdk5 ؊/؊ embryos. The central band of acetylcholine receptor (AChR) clusters is also wider in Cdk5 ؊/؊ diaphragms, together with the absence of S100 immunoreactivity along the phrenic nerve during late embryonic stages. Moreover, we unexpectedly discovered that the agrin-induced formation of large AChR clusters is significantly increased in primary muscle cultures prepared from Cdk5-null mice and in C2C12 myotubes when Cdk5 activity was suppressed. These abnormalities are accompanied by elevated frequency of miniature endplate potentials in Cdk5-null diaphragm. Taken together, our findings reveal the essential role of Cdk5 in regulating the development of motor axons and neuromuscular synapses in vivo.agrin ͉ Cdk5 ͉ ErbB receptor ͉ neuromuscular junction

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Aberrant development of motor axons and neuromuscular synapses in erbB2-deficient mice

Cited by 168 publications

References 35 publications

Aberrant Patterning of Neuromuscular Synapses in Choline Acetyltransferase-Deficient Mice

Aberrant Patterning of Neuromuscular Synapses in Choline Acetyltransferase-Deficient Mice

The epidermal growth factor receptor family: Biology driving targeted therapeutics

Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclin-dependent kinase 5 null mice

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