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

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.

SUBMITTER: Carabalona A

PROVIDER: S-EPMC4731285 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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

Carabalona Aurelie A Hu Daniel Jun-Kit DJ Vallee Richard B RB

Nature neuroscience 20160111 2

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 in ...[more]

PMID: 26752160

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Project description:BackgroundMedulloblastoma (MB) is the most common malignant brain tumor in children. Current problems in the clinic include metastasis, recurrence, and treatment-related sequelae that highlight the need for targeted therapies. Epigenetic perturbations are an established hallmark of human MB and expression of Lysine Specific Demethylase 1 (LSD1) is elevated in MBs compared to normal tissue, suggesting that LSD1 inhibitors may have efficacy against human MB tumors.MethodsExpression of LSD1 was examined across a publicly-available database and correlated with patient outcomes. Sonic Hedgehog (SHH) MB samples were clustered based on expression of LSD1 and LSD1-associated RE-1 silencing transcription factor (REST) target genes as well as genes involved in metastasis. Resulting clusters were examined for patient outcomes associated with LSD1 and REST expression. Human SHH MB cell lines were transduced with a REST-transgene to create isogenic cell pairs. In vitro viability and cell migration assays were used to examine the effect of LSD1 knockdown or inhibition on these parameters.ResultsWe demonstrate that subsets of SHH MB tumors have elevated LSD1 expression coincident with increased expression of its deubiquitylase, USP7, and REST. Patients with co-elevation of USP7, REST, and LSD1 have poorer outcomes compared to those with lower expression of these genes. In SHH MB cell lines, REST elevation increased cell growth and LSD1 protein levels. Surprisingly, while genetic loss of LSD1 reduced cell viability, pharmacological targeting of its activity using LSD1 inhibitors did not affect cell viability. However, a reduction in REST-dependent cell migration was seen in wound healing, suggesting that REST-LSD1 interaction regulates cell migration. Ingenuity pathway analyses validated these findings and identified Hypoxia Inducible Factor 1 alpha (HIF1A) as a potential target. In line with this, ectopic expression of HIF1A rescued the loss of migration seen following LSD1 inhibition.ConclusionsA subset of SHH patients display increased levels of LSD1 and REST, which is associated with poor outcomes. REST elevation in MB in conjunction with elevated LSD1 promotes MB cell migration. LSD1 inhibition blocks REST-dependent cell migration of MB cells in a HIF1A-dependent manner.

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

Publications

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

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