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.
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.
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
-
- 6,885
- views
-
- 820
- downloads
-
- 52
- 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
- Developmental Biology
Mouse oocytes undergo drastic changes in organellar composition and their activities during maturation from the germinal vesicle (GV) to metaphase II (MII) stage. After fertilization, the embryo degrades parts of the maternal components via lysosomal degradation systems, including autophagy and endocytosis, as zygotic gene expression begins during embryogenesis. Here, we demonstrate that endosomal-lysosomal organelles form large spherical assembly structures, termed endosomal-lysosomal organellar assemblies (ELYSAs), in mouse oocytes. ELYSAs are observed in GV oocytes, attaining sizes up to 7–8 μm in diameter in MII oocytes. ELYSAs comprise tubular-vesicular structures containing endosomes and lysosomes along with cytosolic components. Most ELYSAs are also positive for an autophagy regulator, LC3. These characteristics of ELYSA resemble those of ELVA (endolysosomal vesicular assemblies) identified independently. The signals of V1-subunit of vacuolar ATPase tends to be detected on the periphery of ELYSAs in MII oocytes. After fertilization, the localization of the V1-subunit on endosomes and lysosomes increase as ELYSAs gradually disassemble at the 2-cell stage, leading to further acidification of endosomal-lysosomal organelles. These findings suggest that the ELYSA/ELVA maintain endosomal-lysosomal activity in a static state in oocytes for timely activation during early development.
-
- Cell Biology
Dietary protein absorption in neonatal mammals and fishes relies on the function of a specialized and conserved population of highly absorptive lysosome-rich enterocytes (LREs). The gut microbiome has been shown to enhance absorption of nutrients, such as lipids, by intestinal epithelial cells. However, whether protein absorption is also affected by the gut microbiome is poorly understood. Here, we investigate connections between protein absorption and microbes in the zebrafish gut. Using live microscopy-based quantitative assays, we find that microbes slow the pace of protein uptake and degradation in LREs. While microbes do not affect the number of absorbing LRE cells, microbes lower the expression of endocytic and protein digestion machinery in LREs. Using transgene-assisted cell isolation and single cell RNA-sequencing, we characterize all intestinal cells that take up dietary protein. We find that microbes affect expression of bacteria-sensing and metabolic pathways in LREs, and that some secretory cell types also take up protein and share components of protein uptake and digestion machinery with LREs. Using custom-formulated diets, we investigated the influence of diet and LRE activity on the gut microbiome. Impaired protein uptake activity in LREs, along with a protein-deficient diet, alters the microbial community and leads to an increased abundance of bacterial genera that have the capacity to reduce protein uptake in LREs. Together, these results reveal that diet-dependent reciprocal interactions between LREs and the gut microbiome regulate protein absorption.
