The Drosophila KIF1A Homolog unc-104 Is Important for Site-Specific Synapse Maturation
Mutations in the kinesin-3 family member KIF1A have been associated with hereditary spastic paraplegia (HSP), hereditary and sensory autonomic neuropathy type 2 (HSAN2) and non-syndromic intellectual disability (ID). Both autosomal recessive and autosomal dominant forms of inheritance have been repo...
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| Format: | Article |
| Language: | en_US |
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Frontiers Research Foundation
2017
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| Online Access: | http://hdl.handle.net/1721.1/106968 https://orcid.org/0000-0001-7463-977X |
| _version_ | 1826203474207965184 |
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| author | Hannan, Shabab B. Stapper, Zeenna A. Kern, Jeannine V. Jahn, Thomas R. Rasse, Tobias M. Zhang, Yao |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Hannan, Shabab B. Stapper, Zeenna A. Kern, Jeannine V. Jahn, Thomas R. Rasse, Tobias M. Zhang, Yao |
| author_sort | Hannan, Shabab B. |
| collection | MIT |
| description | Mutations in the kinesin-3 family member KIF1A have been associated with hereditary spastic paraplegia (HSP), hereditary and sensory autonomic neuropathy type 2 (HSAN2) and non-syndromic intellectual disability (ID). Both autosomal recessive and autosomal dominant forms of inheritance have been reported. Loss of KIF1A or its homolog unc-104 causes early postnatal or embryonic lethality in mice and Drosophila, respectively. In this study, we use a previously described hypomorphic allele of unc-104, unc-104[superscript bris], to investigate the impact of partial loss-of-function of kinesin-3 on synapse maturation at the Drosophila neuromuscular junction (NMJ). Unc-104[superscript bris] mutants exhibit structural defects where a subset of synapses at the NMJ lack all investigated active zone (AZ) proteins, suggesting a complete failure in the formation of the cytomatrix at the active zone (CAZ) at these sites. Modulating synaptic Bruchpilot (Brp) levels by ectopic overexpression or RNAi-mediated knockdown suggests that the loss of AZ components such as Ca[superscript 2+] channels and Liprin-α is caused by impaired kinesin-3 based transport rather than due to the absence of the key AZ organizer protein, Brp. In addition to defects in CAZ assembly, unc-104[superscript bris] mutants display further defects such as depletion of dense core and synaptic vesicle (SV) markers from the NMJ. Notably, the level of Rab3, which is important for the allocation of AZ proteins to individual release sites, was severely reduced at unc-104[superscript bris] mutant NMJs. Overexpression of Rab3 partially ameliorates synaptic phenotypes of unc-104[superscript bris] larvae, suggesting that lack of presynaptic Rab3 contributes to defects in synapse maturation. |
| first_indexed | 2024-09-23T12:37:36Z |
| format | Article |
| id | mit-1721.1/106968 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:37:36Z |
| publishDate | 2017 |
| publisher | Frontiers Research Foundation |
| record_format | dspace |
| spelling | mit-1721.1/1069682022-10-01T10:08:51Z The Drosophila KIF1A Homolog unc-104 Is Important for Site-Specific Synapse Maturation Hannan, Shabab B. Stapper, Zeenna A. Kern, Jeannine V. Jahn, Thomas R. Rasse, Tobias M. Zhang, Yao Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Picower Institute for Learning and Memory Zhang, Yao Mutations in the kinesin-3 family member KIF1A have been associated with hereditary spastic paraplegia (HSP), hereditary and sensory autonomic neuropathy type 2 (HSAN2) and non-syndromic intellectual disability (ID). Both autosomal recessive and autosomal dominant forms of inheritance have been reported. Loss of KIF1A or its homolog unc-104 causes early postnatal or embryonic lethality in mice and Drosophila, respectively. In this study, we use a previously described hypomorphic allele of unc-104, unc-104[superscript bris], to investigate the impact of partial loss-of-function of kinesin-3 on synapse maturation at the Drosophila neuromuscular junction (NMJ). Unc-104[superscript bris] mutants exhibit structural defects where a subset of synapses at the NMJ lack all investigated active zone (AZ) proteins, suggesting a complete failure in the formation of the cytomatrix at the active zone (CAZ) at these sites. Modulating synaptic Bruchpilot (Brp) levels by ectopic overexpression or RNAi-mediated knockdown suggests that the loss of AZ components such as Ca[superscript 2+] channels and Liprin-α is caused by impaired kinesin-3 based transport rather than due to the absence of the key AZ organizer protein, Brp. In addition to defects in CAZ assembly, unc-104[superscript bris] mutants display further defects such as depletion of dense core and synaptic vesicle (SV) markers from the NMJ. Notably, the level of Rab3, which is important for the allocation of AZ proteins to individual release sites, was severely reduced at unc-104[superscript bris] mutant NMJs. Overexpression of Rab3 partially ameliorates synaptic phenotypes of unc-104[superscript bris] larvae, suggesting that lack of presynaptic Rab3 contributes to defects in synapse maturation. Chica and Heinz Schaller Foundation Hertie Foundation 2017-02-16T17:27:09Z 2017-02-16T17:27:09Z 2016-09 2016-05 Article http://purl.org/eprint/type/JournalArticle 1662-5102 http://hdl.handle.net/1721.1/106968 Zhang, Yao V. et al. “The Drosophila KIF1A Homolog Unc-104 Is Important for Site-Specific Synapse Maturation.” Frontiers in Cellular Neuroscience 10 (2016): n. pag. https://orcid.org/0000-0001-7463-977X en_US http://dx.doi.org/10.3389/fncel.2016.00207 Frontiers in Cellular Neuroscience Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/ application/pdf Frontiers Research Foundation Frontiers |
| spellingShingle | Hannan, Shabab B. Stapper, Zeenna A. Kern, Jeannine V. Jahn, Thomas R. Rasse, Tobias M. Zhang, Yao The Drosophila KIF1A Homolog unc-104 Is Important for Site-Specific Synapse Maturation |
| title | The Drosophila KIF1A Homolog unc-104 Is Important for Site-Specific Synapse Maturation |
| title_full | The Drosophila KIF1A Homolog unc-104 Is Important for Site-Specific Synapse Maturation |
| title_fullStr | The Drosophila KIF1A Homolog unc-104 Is Important for Site-Specific Synapse Maturation |
| title_full_unstemmed | The Drosophila KIF1A Homolog unc-104 Is Important for Site-Specific Synapse Maturation |
| title_short | The Drosophila KIF1A Homolog unc-104 Is Important for Site-Specific Synapse Maturation |
| title_sort | drosophila kif1a homolog unc 104 is important for site specific synapse maturation |
| url | http://hdl.handle.net/1721.1/106968 https://orcid.org/0000-0001-7463-977X |
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