Regulation of neural stem cell proliferation and differentiation by Kinesin family member 2a

Sun, Dong; Zhou, Xue; Yu, Hua; He, Xuming; Guo, Wei; Xiong, Wen Cheng; Zhu, Xinen

doi:10.1371/journal.pone.0179047

Cited by 19 publications

(15 citation statements)

References 38 publications

(42 reference statements)

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“…Misregulation of MT plus ends may also explain the lengthened mitosis observed in DKO BPs. A candidate WNT/STOP target protein is Kif2a (Taelman et al , 2010 ), a MT plus end regulator that is required for cortical neurogenesis (Sun et al , 2017 ; Ding et al , 2019 ). On the other hand, we cannot exclude cross‐talk between WNT/STOP and the WNT/PCP‐pathway, which is also implicated in asymmetric division in cortical progenitors (Delaunay et al , 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Mitotic WNT signalling orchestrates neurogenesis in the developing neocortex

et al. 2021

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The role of WNT/b-catenin signalling in mouse neocortex development remains ambiguous. Most studies demonstrate that WNT/bcatenin regulates progenitor self-renewal but others suggest it can also promote differentiation. Here we explore the role of WNT/ STOP signalling, which stabilizes proteins during G2/M by inhibiting glycogen synthase kinase (GSK3)-mediated protein degradation. We show that mice mutant for cyclin Y and cyclin Y-like 1 (Ccny/l1), key regulators of WNT/STOP signalling, display reduced neurogenesis in the developing neocortex. Specifically, basal progenitors, which exhibit delayed cell cycle progression, were drastically decreased. Ccny/l1-deficient apical progenitors show reduced asymmetric division due to an increase in apical-basal astral microtubules. We identify the neurogenic transcription factors Sox4 and Sox11 as direct GSK3 targets that are stabilized by WNT/STOP signalling in basal progenitors during mitosis and that promote neuron generation. Our work reveals that WNT/STOP signalling drives cortical neurogenesis and identifies mitosis as a critical phase for neural progenitor fate.

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Section: Discussionmentioning

confidence: 99%

Mitotic WNT signalling orchestrates neurogenesis in the developing neocortex

et al. 2021

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“…Neurospheres were prepared and maintained as described previously with slight modification 57 , 58 . Two-month-old male mice ( Neo f/ f and Neo Nestin - CKO) were killed and then dissected DG to culture adult hippocampal NSCs.…”

Section: Methodsmentioning

confidence: 99%

Neogenin, a regulator of adult hippocampal neurogenesis, prevents depressive-like behavior

Sun

Zhao

et al. 2018

Cell Death Dis

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Adult neurogenesis in hippocampal dentate gyrus (DG) is a complex, but precisely controlled process. Dysregulation of this event contributes to multiple neurological disorders, including major depression. Thus, it is of considerable interest to investigate how adult hippocampal neurogenesis is regulated. Here, we present evidence for neogenin, a multifunctional transmembrane receptor, to regulate adult mouse hippocampal neurogenesis. Loss of neogenin in adult neural stem cells (NSCs) or neural progenitor cells (NPCs) impaired NSCs/NPCs proliferation and neurogenesis, whereas increased their astrocytic differentiation. Mechanistic studies revealed a role for neogenin to positively regulate Gli1, a crucial downstream transcriptional factor of sonic hedgehog, and expression of Gli1 into neogenin depleted NSCs/NPCs restores their proliferation. Further morphological and functional studies showed additional abnormities, including reduced dendritic branches and spines, and impaired glutamatergic neuro-transmission, in neogenin-depleted new-born DG neurons; and mice with depletion of neogenin in NSCs/NPCs exhibited depressive-like behavior. These results thus demonstrate unrecognized functions of neogenin in adult hippocampal NSCs/NPCs-promoting NSCs/NPCs proliferation and neurogenesis and preventing astrogliogenesis and depressive-like behavior, and suggest neogenin regulation of Gli1 signaling as a possible underlying mechanism.

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“…Kinesin superfamily proteins (KIFs) are important molecular motors that control MT organization and dynamics in both axons and dendrites and mediate intracellular transport of various cargo, including vesicles, organelles, cellular proteins and mRNAs, along MTs 1,2 . The importance of both the force-generating and MT-regulating functions of KIFs for brain development has become evident with loss of function studies demonstrating defects in mitosis [3][4][5][6][7][8][9] , cytokinesis 10,11 , polarity 3 , migration [12][13][14] , axonal growth and branching [14][15][16][17][18] , survival 19 and synaptogenesis [20][21][22][23][24] . Further reflecting the key role of KIFs in neuronal development, variants in human KIF-encoding genes (KIF4A 24 , KIF7 [25][26][27][28] , KIF11 29 , KIF2A [30][31][32] , KIF5C 24,28,30,33 , KIF1A 28,34 , KIF6 35 , KIF14 11,36,37 , KIF26A…”

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confidence: 99%

Mutations in the KIF21B kinesin gene cause neurodevelopmental disorders through imbalanced canonical motor activity

et al. 2020

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KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynamics. We report three missense variants and one duplication in KIF21B in individuals with neurodevelopmental disorders associated with brain malformations, including corpus callosum agenesis (ACC) and microcephaly. We demonstrate, in vivo, that the expression of KIF21B missense variants specifically recapitulates patients’ neurodevelopmental abnormalities, including microcephaly and reduced intra- and inter-hemispheric connectivity. We establish that missense KIF21B variants impede neuronal migration through attenuation of kinesin autoinhibition leading to aberrant KIF21B motility activity. We also show that the ACC-related KIF21B variant independently perturbs axonal growth and ipsilateral axon branching through two distinct mechanisms, both leading to deregulation of canonical kinesin motor activity. The duplication introduces a premature termination codon leading to nonsense-mediated mRNA decay. Although we demonstrate that Kif21b haploinsufficiency leads to an impaired neuronal positioning, the duplication variant might not be pathogenic. Altogether, our data indicate that impaired KIF21B autoregulation and function play a critical role in the pathogenicity of human neurodevelopmental disorder.

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Regulation of neural stem cell proliferation and differentiation by Kinesin family member 2a

Cited by 19 publications

References 38 publications

Mitotic WNT signalling orchestrates neurogenesis in the developing neocortex

Mitotic WNT signalling orchestrates neurogenesis in the developing neocortex

Neogenin, a regulator of adult hippocampal neurogenesis, prevents depressive-like behavior

Mutations in the KIF21B kinesin gene cause neurodevelopmental disorders through imbalanced canonical motor activity

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