Phosphorylation of CRMP2 is required for migration and positioning of Purkinje cells: Redundant roles of CRMP1 and CRMP4

Yamazaki, Yuki; Nagai, Jun; Akinaga, Satoshi; Koga, Yumeno; Hasegawa, Masaya; Takahashi, Miyuki; Yamashita, Naoya; Kolattukudy, P.E.; Goshima, Yoshio; Ohshima, Toshio

doi:10.1016/j.brainres.2020.146762

Cited by 7 publications

(7 citation statements)

References 39 publications

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“…Lastly, we compared PN markers from human tissue, murine tissue and both the PN and Unknown clusters, identifying 236 genes in common (2.2%, Supplementary Figure S20e and Supplementary Table S35). 21 of these were represented in the Ma’ayan PN gene set 50 , including DCX (previously observed in PNs 51 , 52 ), the Reelin receptor VLDLR , known to be involved with patterning of PN topography 53 , DLGAP4 (known to be expressed by PNs 54 , 55 ), CRMP1 (required for PN migration 56 ) as well as RAB3C and TNFRSF21. NOVA2 , which regulates neuronal migration in PNs 57 was also detected.…”

Section: Resultsmentioning

confidence: 99%

High-resolution transcriptional landscape of xeno-free human induced pluripotent stem cell-derived cerebellar organoids

Nayler

Agarwal

Curion

et al. 2021

Sci Rep

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Current protocols for producing cerebellar neurons from human pluripotent stem cells (hPSCs) often rely on animal co-culture and mostly exist as monolayers, limiting their capability to recapitulate the complex processes in the developing cerebellum. Here, we employed a robust method, without the need for mouse co-culture to generate three-dimensional cerebellar organoids from hPSCs that display hallmarks of in vivo cerebellar development. Single-cell profiling followed by comparison to human and mouse cerebellar atlases revealed the presence and maturity of transcriptionally distinct populations encompassing major cerebellar cell types. Encapsulation with Matrigel aimed to provide more physiologically-relevant conditions through recapitulation of basement-membrane signalling, influenced both growth dynamics and cellular composition of the organoids, altering developmentally relevant gene expression programmes. We identified enrichment of cerebellar disease genes in distinct cell populations in the hPSC-derived cerebellar organoids. These findings ascertain xeno-free human cerebellar organoids as a unique model to gain insight into cerebellar development and its associated disorders.

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Section: Resultsmentioning

confidence: 99%

High-resolution transcriptional landscape of xeno-free human induced pluripotent stem cell-derived cerebellar organoids

Nayler

Agarwal

Curion

et al. 2021

Sci Rep

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“…SUMOylation of CRMP2 regulates interaction with calcium channels [33] and sodium channels [32], and phosphorylation and SUMOylation together modulate the function of CRMP2 in regulating the formation and maturation of dendritic spines [34]. CRMP4 is phosphorylated by a variety of kinases, including GSK-3, to regulate neurite outgrowth [35], migration, and positioning [36], as well as Cdk5 and DYRK2 to regulate neurulation [37]. Whether and how the phosphorylation of CRMP4 affects SUMOylation and how upstream kinases such as GSK-3, Cdk5, or other kinases modulate CRMP4 activity remain to be further explored.…”

Section: Discussionmentioning

confidence: 99%

The impact of CRMP4 SUMOylation on the Cav1.2 interaction, neurite outgrowth and thermal pain sensitivity

Lai

Pan

Liao

et al. 2021

J. Integr. Neurosci.

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Collapsin response mediator protein 4 (CRMP4) is critical for neuronal development. However, whether CRMP4 could be SUMOylated and how the SUMOylation regulates the interaction with the L-type voltage-gated calcium channel (Cav1.2), neurite outgrowth, and thermal pain sensitivity remain to be elucidated. To determine the SUMOylation of CRMP4, Glutathione S-transferase (GST) -Small Ubiquitin-like Modifier 1 (-SUMO1), -SUMO2, and -SUMO3 proteins were purified for GST-pulldown. Immunofluorescence staining was performed to observe colocalization of CRMP4 and SUMOs. Coimmunoprecipitation (co-IP) was performed to assess the interaction between CRMP4 and SUMO2. GST-pulldown and co-IP were performed to verify the interaction between CRMP4 and Cav1.2. The impact of SUMOylation of CRMP4 on its interaction with Cav1.2 was determined. Then, the effect of CRMP4 SUMOylation on neurite outgrowth was observed. Whole-cell patch clamping revealed the effect of CRMP4 SUMOylation on Cav1.2 mediated calcium influx. Paw withdrawal latency was measured to assess the impact of CRMP4 SUMOylation on thermal pain sensitivity in rats. The data revealed that CRMP4 K374 is a potential site for SUMO modification. SUMO1, SUMO2, and SUMO3 can all interact with CRMP4. SUMO2 interacts with CRMP4, but not a variant of CRMP4 harboring a mutation of K374. CRMP4 and SUMO proteins colocalized in neurites, and CRMP4 deSUMOylation promoted neurite outgrowth. CRMP4 interacted with Cav1.2, and deSUMOylation of CRMP4 strengthened this interaction. CRMP4 promoted calcium influx via Cav1.2, and overexpression of CRMP4 significantly increased thermal pain sensitivity in rats, which CRMP4 deSUMOylation strengthened. In conclusion, these data demonstrate the SUMOylation of CRMP4, elucidate the impacts of SUMOylation on the interaction with Cav1.2 on neurite outgrowth and thermal pain sensitivity.

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“…Alternatively, it has been suggested that the antagonistic roles of CRMP4 observed in distinct neuronal populations could be due to differences in its phosphorylation state (Tanaka, Morimura, & Ohshima, 2012). CRMP4-KO mice display dendritic arborization defects in hippocampal CA1 and cortical pyramidal neurons, mispositioning of Purkinje cells, and olfactory bulb lamination defects (Takaya et al, 2016;Tsutiya et al, 2016;Yamazaki et al, 2020). Here, we additionally show that a knockout of CRMP4 is associated with a defect in post-commissural fornix development, leading to a reduction of this tract associated with fasciculation defects persisting into adulthood.…”

Section: Discussionmentioning

confidence: 99%

CRMP4-mediated fornix development involves Semaphorin-3E signaling pathway

Boulan

Ravanello

Peyrel

et al. 2021

eLife

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Neurodevelopmental axonal pathfinding plays a central role in correct brain wiring and subsequent cognitive abilities. Within the growth cone, various intracellular effectors transduce axonal guidance signals by remodeling the cytoskeleton. Semaphorin-3E (Sema3E) is a guidance cue implicated in development of the fornix, a neuronal tract connecting the hippocampus to the hypothalamus. Microtubule-Associated Protein 6 (MAP6) has been shown to be involved in the Sema3E growth-promoting signaling pathway. In this study, we identified the Collapsin Response Mediator Protein 4 (CRMP4) as a MAP6 partner and a crucial effector in Sema3E growth-promoting activity. CRMP4-KO mice displayed abnormal fornix development reminiscent of that observed in Sema3E-KO mice. CRMP4 was shown to interact with the Sema3E tripartite receptor complex within Detergent-Resistant Membrane (DRM) domains, and DRM domain integrity was required to transduce Sema3E signaling through the Akt/GSK3 pathway. Finally, we showed that the cytoskeleton-binding domain of CRMP4 is required for Sema3E's growth-promoting activity, suggesting that CRMP4 plays a role at the interface between Sema3E receptors, located in DRM domains, and the cytoskeleton network. As the fornix is affected in many psychiatric diseases, such as schizophrenia, our results provide new insights to better understand the neurodevelopmental components of these diseases.

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Phosphorylation of CRMP2 is required for migration and positioning of Purkinje cells: Redundant roles of CRMP1 and CRMP4

Cited by 7 publications

References 39 publications

High-resolution transcriptional landscape of xeno-free human induced pluripotent stem cell-derived cerebellar organoids

High-resolution transcriptional landscape of xeno-free human induced pluripotent stem cell-derived cerebellar organoids

The impact of CRMP4 SUMOylation on the Cav1.2 interaction, neurite outgrowth and thermal pain sensitivity

CRMP4-mediated fornix development involves Semaphorin-3E signaling pathway

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