Specific depletion of the motor protein KIF5B leads to deficits in dendritic transport, synaptic plasticity and memory
- University of Hong Kong, Hong Kong
- Chinese University of Hong Kong, Hong Kong
Abstract
The kinesin I family of motor proteins are crucial for axonal transport, but their roles in dendritic transport and postsynaptic function are not well-defined. Gene duplication and subsequent diversification give rise to three homologous kinesin I proteins (KIF5A, KIF5B and KIF5C) in vertebrates, but it is not clear whether and how they exhibit functional specificity. Here we show that knockdown of KIF5A or KIF5B differentially affects excitatory synapses and dendritic transport in hippocampal neurons. The functional specificities of the two kinesins are determined by their diverse carboxyl-termini, where arginine methylation occurs in KIF5B and regulates its function. KIF5B conditional knockout mice exhibit deficits in dendritic spine morphogenesis, synaptic plasticity and memory formation. Our findings provide insights into how expansion of the kinesin I family during evolution leads to diversification and specialization of motor proteins in regulating postsynaptic function.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
Research Grant Council of Hong Kong (GRF 16100814)
- Kwok-On Lai
Shenzhen Peacock Team Project (KQTD2015033117210153)
- Jiandong Huang
Shenzhen Science Technology Innovation Committee Basic Science Research Grant (JCYJ20170413154523577)
- Jiandong Huang
University Grants Committee of Hong Kong (AoE/M-604/16)
- Wing-Ho Yung
University Grants Committee of Hong Kong (T13-605/18-W)
- Kwok-On Lai
Research Grant Council of Hong Kong (GRF 17135816)
- Kwok-On Lai
Research Grant Council of Hong Kong (GRF 17106018)
- Kwok-On Lai
Research Grant Council of Hong Kong (ECS 27119715)
- Kwok-On Lai
University Grants Committee of Hong Kong (AoE/M-604/16)
- Kwok-On Lai
Research Grant Council of Hong Kong (ECS 27103715)
- Cora Sau Wan Lai
Research Grant Council of Hong Kong (GRF 17128816)
- Cora Sau Wan Lai
National Natural Science Foundation of China (NSFC/General Program 31571031)
- Cora Sau Wan Lai
Health and Medical Research Fund Hong Kong (03143096)
- Cora Sau Wan Lai
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Eunjoon Kim, Institute for Basic Science, Korea Advanced Institute of Science and Technology, Republic of Korea
Ethics
Animal experimentation: All experiments were approved and performed in accordance with University of Hong Kong Committee on the Use of Live Animals (CULATR 3935-16 and CULATR 4056-16) and in Teaching and Research guidelines.
Version history
- Received: November 8, 2019
- Accepted: January 20, 2020
- Accepted Manuscript published: January 21, 2020 (version 1)
- Version of Record published: February 18, 2020 (version 2)
Copyright
© 2020, Zhao et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 6,334
- views
-
- 780
- downloads
-
- 44
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Specific depletion of the motor protein KIF5B leads to deficits in dendritic transport, synaptic plasticity and memory
eLife 9:e53456.
https://doi.org/10.7554/eLife.53456
Further reading
-
- Cell Biology
Elastic cartilage constitutes a major component of the external ear, which functions to guide sound to the middle and inner ears. Defects in auricle development cause congenital microtia, which affects hearing and appearance in patients. Mutations in several genes have been implicated in microtia development, yet, the pathogenesis of this disorder remains incompletely understood. Here, we show that Prrx1 genetically marks auricular chondrocytes in adult mice. Interestingly, BMP-Smad1/5/9 signaling in chondrocytes is increasingly activated from the proximal to distal segments of the ear, which is associated with a decrease in chondrocyte regenerative activity. Ablation of Bmpr1a in auricular chondrocytes led to chondrocyte atrophy and microtia development at the distal part. Transcriptome analysis revealed that Bmpr1a deficiency caused a switch from the chondrogenic program to the osteogenic program, accompanied by enhanced protein kinase A activation, likely through increased expression of Adcy5/8. Inhibition of PKA blocked chondrocyte-to-osteoblast transformation and microtia development. Moreover, analysis of single-cell RNA-seq of human microtia samples uncovered enriched gene expression in the PKA pathway and chondrocyte-to-osteoblast transformation process. These findings suggest that auricle cartilage is actively maintained by BMP signaling, which maintains chondrocyte identity by suppressing osteogenic differentiation.
-
- Cancer Biology
- Cell Biology
Internalization from the cell membrane and endosomal trafficking of receptor tyrosine kinases (RTKs) are important regulators of signaling in normal cells that can frequently be disrupted in cancer. The adrenal tumor pheochromocytoma (PCC) can be caused by activating mutations of the rearranged during transfection (RET) receptor tyrosine kinase, or inactivation of TMEM127, a transmembrane tumor suppressor implicated in trafficking of endosomal cargos. However, the role of aberrant receptor trafficking in PCC is not well understood. Here, we show that loss of TMEM127 causes wildtype RET protein accumulation on the cell surface, where increased receptor density facilitates constitutive ligand-independent activity and downstream signaling, driving cell proliferation. Loss of TMEM127 altered normal cell membrane organization and recruitment and stabilization of membrane protein complexes, impaired assembly, and maturation of clathrin-coated pits, and reduced internalization and degradation of cell surface RET. In addition to RTKs, TMEM127 depletion also promoted surface accumulation of several other transmembrane proteins, suggesting it may cause global defects in surface protein activity and function. Together, our data identify TMEM127 as an important determinant of membrane organization including membrane protein diffusability and protein complex assembly and provide a novel paradigm for oncogenesis in PCC where altered membrane dynamics promotes cell surface accumulation and constitutive activity of growth factor receptors to drive aberrant signaling and promote transformation.
