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KIF1A inhibition immortalizes brain stem cells but blocks BDNF-mediated neuronal migration

Nature Neuroscience volume 19, pages 253–262 (2016)Cite this article

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Abstract

Brain neural stem cells (radial glial progenitors, RGPs) undergo a mysterious form of cell cycle–entrained interkinetic nuclear migration (INM) that is driven apically by cytoplasmic dynein and basally by the kinesin KIF1A, which has recently been implicated in human brain developmental disease. To understand the consequences of altered basal INM and the roles of KIF1A in disease, we performed constitutive and conditional RNAi and expressed mutant KIF1A in E16 to P7 rat RGPs and neurons. RGPs inhibited in basal INM still showed normal cell cycle progression, although neurogenic divisions were severely reduced. Postmitotic neuronal migration was independently disrupted at the multipolar stage and accompanied by premature ectopic expression of neuronal differentiation markers. Similar effects were unexpectedly observed throughout the layer of surrounding control cells, mimicked by Bdnf (brain-derived neurotrophic factor) or Dcx RNAi, and rescued by BDNF application. These results identify sequential and independent roles for KIF1A and provide an important new approach for reversing the effects of human disease.

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Figure 1: Kif1a RNAi inhibition of basal nuclear migration in RGP cells has no effect on cell cycle progression.
Figure 2: RGP cells exhibit persistent symmetric divisions despite basal migration arrest.
Figure 3: Cell-autonomous and non-autonomous effects in neuronal morphogenesis and gene expression.
Figure 4: Cell autonomous and non-autonomous effects on neuronal markers at P7.
Figure 5: Sequential electroporation test for non-cell-autonomous effects of Kif1a RNAi.
Figure 6: Conditional, cell stage–specific RNAi supports distinct sequential roles for Kif1a during brain development.
Figure 7: Effect of KIF1A R18W human mutation on INM and neuronal migration.
Figure 8: Role of BDNF in KIF1A pathway.

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Acknowledgements

We thank F. Polleux, H. Wichterle, J. Goldman and T. Dantas for critical reading and input to our manuscript. We thank G. Krietzer (Cell and Developmental Biology, Weill Cornell Medical College), C. Cardoso and A. Falace (Institut de Neurobiologie de la Méditerranée INSERM UMR901) for reagents. We thank A. Represa, C. Pellegrino and D. Doobin for advice. This project was supported by US National Institutes of Health grant HD40182 to R.B.V.

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  1. Department of Pathology and Cell Biology, Columbia University, New York, New York, USA

    Aurelie Carabalona, Daniel Jun-Kit Hu & Richard B Vallee

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  1. Aurelie Carabalona
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Contributions

A.C. and R.B.V. conceived the project and wrote the manuscript. A.C. and D.J.-K.H. performed experiments and analyzed data. All of the authors read and approved the final manuscript.

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Correspondence to Aurelie Carabalona or Richard B Vallee.

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Integrated supplementary information

Supplementary Figure 1 Kif1a RNAi effect on basal progenitor differentiation

Related to Figure 2. Representative confocal images of the VZ and SVZ of rat cortices transfected at E16 with scrambled or Kif1a shRNA, and immunostained 4 days later for intermediate progenitor marker, Tbr2 (n=5 for scramble and Kif1a shRNA). The percentage of Tbr2+/GFP transfected cells was significantly reduced in Kif1a knockdown brains compared to control. SVZ: subventricular zone; VZ: ventricular zone. Scale bars 15µm.

Supplementary Figure 2 Common effects of different Kif1a vectors

Related to Figure 4. A and B. Representative coronal sections of E20 rat brains injected at E16 with two different control and shRNA constructs. Scramble and Kif1a-shRNA was cloned into the pRNAT-U6.1/Neo-GFP (A), or into the mU6pro vector and co-injected with pCAG-RFP (B). Kif1a shRNAs in either vector resulted in a similar accumulation of multipolar neurons in the SVZ / lower IZ. CP: cortical plate; IZ: intermediate zone; SVZ: subventricular zone; VZ: ventricular zone. Scale bars 100μm.

Supplementary Figure 3 Non-cell-autonomous effect of RNAi for Dcx but not nuclear envelope dynein recruitment factors

Related to Figure 3. E16 rat embryonic brains were subjected to in utero electroporation with shRNAs for BicD2, Nup133, Cenp-F, Dcx, or TrkB. Brain slices were stained at E20 for anti-Tbr1. Expression of BicD2, Nup133, Cenp-F, Dcx, and Trkb shRNAs resulted in a marked reduction of electroporated cells in the IZ and the CP, with many cell bodies in the SVZ retaining a multipolar morphology. Non-transfected cells expressing Tbr1 were still distributed normally within the upper IZ/lower CP for BicD2, Nup133, Cenp-F, and TrkB shRNAs. However, DCX shRNA resulted in Tbr1 expression in non-transfected cells within the SVZ/lower IZ, suggesting a non-cell autonomous effect. CP: cortical plate; IZ: intermediate zone; SVZ: subventricular zone; VZ: ventricular zone. Scale bar 50μm.

Supplementary Figure 4 Limited overlap of sequentially versus cotransfected cells

Related to Figure 5. A and B. Representative coronal sections of E20 rat brains at E16 co-injected (A) or sequentially injected (B) with RFP and GFP plasmids. (A) Co-transfection with plasmids encoding RFP and GFP resulted in the majority of transfected cells to be double-labeled (yellow) while sequential transfection (B) labels largely non-overlapping cell populations. CP: cortical plate; IZ: intermediate zone. Scale bars 100μm.

Supplementary Figure 5 Kif1a RNAi does not affect radial glial cell morphology and organization

Representative coronal sections of E20 rat brains transfected at E16 with scrambled or Kif1a shRNA, and immunostained 4 days later for the intermediate filament marker, vimentine (A); or transfected at E16 with BLBP-GFP alone or in combination with Kif1a shRNA (B). No disruption in the organization of radial glial fibers was observed in brains subjected to Kif1a RNAi, with both basal and apical processes resembling those observed in control. CP: cortical plate; IZ: intermediate zone; SVZ: subventricular zone; VZ: ventricular zone. Scale bars 100μm.

Supplementary Figure 6 BDNF does not rescue INM but rescues non-cell-autonomous neuronal effect

Related to Figure 8. E19 coronal rat brain slices electroporated at E16 with Dcx shRNA (A), NeuroD-cre + Kif1a shRNA (B), the human mutation R18W (C), or Kif1a shRNA (D), and cultured for 24 hours in the presence of recombinant BDNF (50 ng/ml) in PBS, or control vehicle alone, and then fixed and examined by microscopy. A-C. BDNF treatment rescued the non-cell autonomous effect caused by Dcx shRNA (A), conditional knockdown of Kif1a specifically in neurons (NeuroD-cre + Kif1a-shRNA; B), and the human mutation R18W (C), as evidenced by restoration of migration in non-transfected cells and normal Tbr1 distribution. D. BDNF treatment does not rescue the INM defect caused by Kif1a shRNA. E. Quantification of the distance of RGP nuclei from the ventricular surface (VS) at E19 ((0-10: Kif1A shRNA+PBS 53.4 ± 5.5%, Kif1A shRNA+BDNF 50.06 ± 3.7%, p=0.4857; 10-20: Kif1A shRNA+PBS 19.66 ± 3.3%, Kif1A shRNA+BDNF 24.59 ± 1.04%, p=0.286; 20-30: Kif1A shRNA+PBS 14.72 ± 1%, Kif1A shRNA+BDNF 15.38 ± 2.7%, p=0.3429; >30: Kif1A shRNA+PBS 12.21 ± 3.5%, Kif1A shRNA+BDNF 9.97 ± 1.7%, p=0.3429; n=4 for scramble and Kif1a shRNA), revealing that RGP nuclei still remain accumulated at the VS after BDNF treatment. Scale bars 15μm (A) 100μm (C, D and E).

Supplementary Figure 7 Bdnf KD does not affect INM at E20 but affects neuronal migration at P7

Related to Figure 8. Coronal rat brain slices electroporated at E16 with Bdnf shRNA and analyzed at E20 (A), or P7 (C). A and B. E20 brain sections stained with RGP cell marker, Pax6 (A) and neuronal marker, TuJ1. The high magnification panels show examples of Pax6 and Tuj1 positive cells (arrows). There is no significant difference between the percentage of RGP cells or neurons electroporated with control or Bdnf shRNA, suggesting that Bdnf shRNA does not affect the ratio of symmetric vs asymmetric divisons. C. Immunostaining for the neuronal marker, NeuN and the upper cortical layer marker CDP, at P7 reveal a distribution of the transfected cells through the white matter and the 6 layers after Bdnf RNAi, but no non-cell autonomous effect. D. Diagrammatic representation of normal and KIF1A/BDNF-altered neurogenesis and migration. Upper panel: temporal progression of control (white) RGP cell behavior, showing cell cycle-dependent nuclear oscillations (INM), followed by symmetric or asymmetric mitotic division and, in the latter case, migration to the multipolar stage in the SVZ/lower IZ and ultimately, to differentiating bipolar neurons in the CP, where Tbr1 (green) is normally expressed. Lower panel: Kif1a knockdown RGP cells (blue) progress through cell cycle without nuclear oscillations and exhibit far fewer asymmetric mitotic divisions. Post-mitotic neurons arrest at the multipolar stage in the SVZ/lower IZ, but prematurely express Tbr1. Surrounding control cells (white) also exhibit migration arrest and ectopic Tbr1 expression, an effect phenocopied by Bdnf knockdown and strikingly rescued by BDNF addition. CP: cortical plate; IZ: intermediate zone; SVZ: subventricular zone; VZ: ventricular zone; WM: white matter. Scale bars 100μm (A, C and E), 15 μm (inset).

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Symmetric division of Kif1a-depleted RGP cell

Related to Figure 2. E16 rat embryonic brain was electroporated with vectors expressing Kif1a shRNA and DsRed-Centrin II. Brain was sectioned at E19 and imaged every 15 minutes. Nucleus of RGP cell apically migrated to the ventricular surface and underwent symmetric division. Nuclei of daughter RGP cells exhibited minimal basal movement. Centrosomes were retained near the apical process. (AVI 1438 kb)

Asymmetric division of Kif1a-depleted RGP cell

Related to Figure 2. E16 rat embryonic brain was electroporated with vectors expressing Kif1a shRNA and DsRed-Centrin II. Brain was sectioned at E19 and imaged every 15 minutes. Nucleus of RGP cell apically migrated to the apical surface and underwent asymmetric division. Nucleus of daughter RGP cells exhibited minimal basal movement while the daughter neuron, as determined by a lack of an apical process and a basally located centrosome, migrated away from the ventricular surface. (AVI 875 kb)

Multipolar-to-Bipolar transition of control neuron

Related to Figure 3. E16 rat embryonic brain was electroporated with vectors expressing Kif1a scramble. Brain was sectioned at E19, imaged every 15 minutes and cultured for ~40 hr during which we monitored, within the SVZ-lower IZ, control multipolar cell converting to a bipolar morphology by 15 hours. (AVI 2087 kb)

Kif1a depleted neurons remain at the multipolar stage

Related to Figure 3. E16 rat embryonic brain was electroporated with vectors expressing Kif1a shRNA. Brain was sectioned at E19, imaged every 15 minutes and cultured for ~40 hr during which we monitored, within the SVZ-lower IZ, absence of the multipolar-to-bipolar transition in Kif1a knockdown cells. (AVI 6503 kb)

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Carabalona, A., Hu, DK. & Vallee, R. KIF1A inhibition immortalizes brain stem cells but blocks BDNF-mediated neuronal migration. Nat Neurosci 19, 253–262 (2016). https://doi.org/10.1038/nn.4213

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