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Motor and Sensory Deficits in the teetering Mice Result from Mutation of the ESCRT Component HGS.

Watson JA, Bhattacharyya BJ, Vaden JH, Wilson JA, Icyuz M, Howard AD, Phillips E, DeSilva TM, Siegal GP, Bean AJ, King GD, Phillips SE, Miller RJ, Wilson SM - PLoS Genet. (2015)

Bottom Line: These structural changes were accompanied by a reduction in spontaneous and evoked release of acetylcholine, indicating a deficit in neurotransmitter release at the NMJ.These deficits in synaptic transmission were associated with elevated levels of ubiquitinated proteins in the synaptosome fraction.Our results indicate that HGS has multiple roles in the nervous system and demonstrate a previously unanticipated requirement for ESCRTs in the maintenance of synaptic transmission.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, University of Alabama at Birmingham, Evelyn F. McKnight Brain Institute, Civitan International Research Center, Birmingham, Alabama, United States of America.

ABSTRACT
Neurons are particularly vulnerable to perturbations in endo-lysosomal transport, as several neurological disorders are caused by a primary deficit in this pathway. In this report, we used positional cloning to show that the spontaneously occurring neurological mutation teetering (tn) is a single nucleotide substitution in hepatocyte growth factor-regulated tyrosine kinase substrate (Hgs/Hrs), a component of the endosomal sorting complex required for transport (ESCRT). The tn mice exhibit hypokenesis, muscle weakness, reduced muscle size and early perinatal lethality by 5-weeks of age. Although HGS has been suggested to be essential for the sorting of ubiquitinated membrane proteins to the lysosome, there were no alterations in receptor tyrosine kinase levels in the central nervous system, and only a modest decrease in tropomyosin receptor kinase B (TrkB) in the sciatic nerves of the tn mice. Instead, loss of HGS resulted in structural alterations at the neuromuscular junction (NMJ), including swellings and ultra-terminal sprouting at motor axon terminals and an increase in the number of endosomes and multivesicular bodies. These structural changes were accompanied by a reduction in spontaneous and evoked release of acetylcholine, indicating a deficit in neurotransmitter release at the NMJ. These deficits in synaptic transmission were associated with elevated levels of ubiquitinated proteins in the synaptosome fraction. In addition to the deficits in neuronal function, mutation of Hgs resulted in both hypermyelinated and dysmyelinated axons in the tn mice, which supports a growing body of evidence that ESCRTs are required for proper myelination of peripheral nerves. Our results indicate that HGS has multiple roles in the nervous system and demonstrate a previously unanticipated requirement for ESCRTs in the maintenance of synaptic transmission.

No MeSH data available.


Related in: MedlinePlus

Distribution of HGS in sciatic nerves of 4-week-old Hgs+/+mice.Top panel, cross sections of sciatic nerves stained with antibodies against neurofilament (NF, green) and HGS (red). Bottom panel, sciatic nerves were stained with antibodies to the Schwann cell marker S100β (green) and HGS (red). Scale bar, 10 μm.
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pgen.1005290.g006: Distribution of HGS in sciatic nerves of 4-week-old Hgs+/+mice.Top panel, cross sections of sciatic nerves stained with antibodies against neurofilament (NF, green) and HGS (red). Bottom panel, sciatic nerves were stained with antibodies to the Schwann cell marker S100β (green) and HGS (red). Scale bar, 10 μm.

Mentions: The changes in myelination that were observed in the Hgstn/tn mice could be attributed to loss of HGS in either axons or Schwann cells. However, when we examined HGS expression in the sciatic nerves of wild type mice by indirect immunofluorescence (Fig 6), we found that HGS staining did not overlap with the neurofilament staining in sciatic nerve axons. Rather, when Schwann cells were visualized with antibodies to the cytoplasmic protein S100β, HGS localized to the external boundary of the Schwann cell body. These findings are in agreement with a previous study detecting HGS transcripts in Schwann cells [49].


Motor and Sensory Deficits in the teetering Mice Result from Mutation of the ESCRT Component HGS.

Watson JA, Bhattacharyya BJ, Vaden JH, Wilson JA, Icyuz M, Howard AD, Phillips E, DeSilva TM, Siegal GP, Bean AJ, King GD, Phillips SE, Miller RJ, Wilson SM - PLoS Genet. (2015)

Distribution of HGS in sciatic nerves of 4-week-old Hgs+/+mice.Top panel, cross sections of sciatic nerves stained with antibodies against neurofilament (NF, green) and HGS (red). Bottom panel, sciatic nerves were stained with antibodies to the Schwann cell marker S100β (green) and HGS (red). Scale bar, 10 μm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482608&req=5

pgen.1005290.g006: Distribution of HGS in sciatic nerves of 4-week-old Hgs+/+mice.Top panel, cross sections of sciatic nerves stained with antibodies against neurofilament (NF, green) and HGS (red). Bottom panel, sciatic nerves were stained with antibodies to the Schwann cell marker S100β (green) and HGS (red). Scale bar, 10 μm.
Mentions: The changes in myelination that were observed in the Hgstn/tn mice could be attributed to loss of HGS in either axons or Schwann cells. However, when we examined HGS expression in the sciatic nerves of wild type mice by indirect immunofluorescence (Fig 6), we found that HGS staining did not overlap with the neurofilament staining in sciatic nerve axons. Rather, when Schwann cells were visualized with antibodies to the cytoplasmic protein S100β, HGS localized to the external boundary of the Schwann cell body. These findings are in agreement with a previous study detecting HGS transcripts in Schwann cells [49].

Bottom Line: These structural changes were accompanied by a reduction in spontaneous and evoked release of acetylcholine, indicating a deficit in neurotransmitter release at the NMJ.These deficits in synaptic transmission were associated with elevated levels of ubiquitinated proteins in the synaptosome fraction.Our results indicate that HGS has multiple roles in the nervous system and demonstrate a previously unanticipated requirement for ESCRTs in the maintenance of synaptic transmission.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, University of Alabama at Birmingham, Evelyn F. McKnight Brain Institute, Civitan International Research Center, Birmingham, Alabama, United States of America.

ABSTRACT
Neurons are particularly vulnerable to perturbations in endo-lysosomal transport, as several neurological disorders are caused by a primary deficit in this pathway. In this report, we used positional cloning to show that the spontaneously occurring neurological mutation teetering (tn) is a single nucleotide substitution in hepatocyte growth factor-regulated tyrosine kinase substrate (Hgs/Hrs), a component of the endosomal sorting complex required for transport (ESCRT). The tn mice exhibit hypokenesis, muscle weakness, reduced muscle size and early perinatal lethality by 5-weeks of age. Although HGS has been suggested to be essential for the sorting of ubiquitinated membrane proteins to the lysosome, there were no alterations in receptor tyrosine kinase levels in the central nervous system, and only a modest decrease in tropomyosin receptor kinase B (TrkB) in the sciatic nerves of the tn mice. Instead, loss of HGS resulted in structural alterations at the neuromuscular junction (NMJ), including swellings and ultra-terminal sprouting at motor axon terminals and an increase in the number of endosomes and multivesicular bodies. These structural changes were accompanied by a reduction in spontaneous and evoked release of acetylcholine, indicating a deficit in neurotransmitter release at the NMJ. These deficits in synaptic transmission were associated with elevated levels of ubiquitinated proteins in the synaptosome fraction. In addition to the deficits in neuronal function, mutation of Hgs resulted in both hypermyelinated and dysmyelinated axons in the tn mice, which supports a growing body of evidence that ESCRTs are required for proper myelination of peripheral nerves. Our results indicate that HGS has multiple roles in the nervous system and demonstrate a previously unanticipated requirement for ESCRTs in the maintenance of synaptic transmission.

No MeSH data available.


Related in: MedlinePlus