The role of von Hippel–Lindau protein in the differentiation of neural progenitor cells under normoxic and anoxic conditions

Tanaka, Yoshihide; Kanno, Hiroshi; Dezawa, Mari; Mimura, Toshiro; Kubo, Atsuhiko; Yamamoto, Isao

doi:10.1016/j.neulet.2005.03.056

Cited by 8 publications

(3 citation statements)

References 12 publications

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“…The division and differentiation of these endogenous NSCs can be regulated by physiological stimuli and pathological conditions [5]. Enhanced neurogenesis has been reported in hypoxic NPCs in vitro [6], [7] and in ischemic brains of neonatal mice [8], adult rats [9] and aged humans in vivo [10]. For examples, exposure to 1–5% oxygen concentration improved NPCs proliferation, survival and dopaminergic neuron development [11], [12].…”

Section: Introductionmentioning

confidence: 99%

Caveolin-1 Plays a Crucial Role in Inhibiting Neuronal Differentiation of Neural Stem/Progenitor Cells via VEGF Signaling-Dependent Pathway

Luo

Lau

et al. 2011

PLoS ONE

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In the present study, we aim to elucidate the roles of caveolin-1(Cav-1), a 22 kDa protein in plasma membrane invaginations, in modulating neuronal differentiation of neural progenitor cells (NPCs). In the hippocampal dentate gyrus, we found that Cav-1 knockout mice revealed remarkably higher levels of vascular endothelial growth factor (VEGF) and the more abundant formation of newborn neurons than wild type mice. We then studied the potential mechanisms of Cav-1 in modulating VEGF signaling and neuronal differentiation in isolated cultured NPCs under normoxic and hypoxic conditions. Hypoxic embryonic rat NPCs were exposed to 1% O2 for 24 h and then switched to 21% O2 for 1, 3, 7 and 14 days whereas normoxic NPCs were continuously cultured with 21% O2. Compared with normoxic NPCs, hypoxic NPCs had down-regulated expression of Cav-1 and up-regulated VEGF expression and p44/42MAPK phosphorylation, and enhanced neuronal differentiation. We further studied the roles of Cav-1 in inhibiting neuronal differentiation by using Cav-1 scaffolding domain peptide and Cav-1-specific small interfering RNA. In both normoxic and hypoxic NPCs, Cav-1 peptide markedly down-regulated the expressions of VEGF and flk1, decreased the phosphorylations of p44/42MAPK, Akt and Stat3, and inhibited neuronal differentiation, whereas the knockdown of Cav-1 promoted the expression of VEGF, phosphorylations of p44/42MAPK, Akt and Stat3, and stimulated neuronal differentiation. Moreover, the enhanced phosphorylations of p44/42MAPK, Akt and Stat3, and neuronal differentiation were abolished by co-treatment of VEGF inhibitor V1. These results provide strong evidence to prove that Cav-1 can inhibit neuronal differentiation via down-regulations of VEGF, p44/42MAPK, Akt and Stat3 signaling pathways, and that VEGF signaling is a crucial target of Cav-1. The hypoxia-induced down-regulation of Cav-1 contributes to enhanced neuronal differentiation in NPCs.

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Section: Introductionmentioning

confidence: 99%

Caveolin-1 Plays a Crucial Role in Inhibiting Neuronal Differentiation of Neural Stem/Progenitor Cells via VEGF Signaling-Dependent Pathway

Luo

Lau

et al. 2011

PLoS ONE

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“…Consequently, the percentage of the neuronal marker MAP-positive cells decreased under hypoxic conditions, but the percentage of the astroglial marker GFAP-positive cells increased. VHL protein dysfunction due to hypoxia may result in the inhibition of neuronal differentiation [ 151 ]. Since VHL does not function under hypoxia, HIF is not degraded, and downstream transcription factors are induced, suggesting that HIF may be involved in the differentiation of NSCs into glia.…”

Section: Characteristics Of Vhl Proteins and Their Roles In Neuronal ...mentioning

confidence: 99%

Role of SOCS and VHL Proteins in Neuronal Differentiation and Development

Kanno

Matsumoto

Yoshizumi

et al. 2023

IJMS

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The basic helix–loop–helix factors play a central role in neuronal differentiation and nervous system development, which involve the Notch and signal transducer and activator of transcription (STAT)/small mother against decapentaplegic signaling pathways. Neural stem cells differentiate into three nervous system lineages, and the suppressor of cytokine signaling (SOCS) and von Hippel-Lindau (VHL) proteins are involved in this neuronal differentiation. The SOCS and VHL proteins both contain homologous structures comprising the BC-box motif. SOCSs recruit Elongin C, Elongin B, Cullin5(Cul5), and Rbx2, whereas VHL recruits Elongin C, Elongin B, Cul2, and Rbx1. SOCSs form SBC-Cul5/E3 complexes, and VHL forms a VBC-Cul2/E3 complex. These complexes degrade the target protein and suppress its downstream transduction pathway by acting as E3 ligases via the ubiquitin–proteasome system. The Janus kinase (JAK) is the main target protein of the E3 ligase SBC-Cul5, whereas hypoxia-inducible factor is the primary target protein of the E3 ligase VBC-Cul2; nonetheless, VBC-Cul2 also targets the JAK. SOCSs not only act on the ubiquitin–proteasome system but also act directly on JAKs to suppress the Janus kinase–signal transduction and activator of transcription (JAK-STAT) pathway. Both SOCS and VHL are expressed in the nervous system, predominantly in brain neurons in the embryonic stage. Both SOCS and VHL induce neuronal differentiation. SOCS is involved in differentiation into neurons, whereas VHL is involved in differentiation into neurons and oligodendrocytes; both proteins promote neurite outgrowth. It has also been suggested that the inactivation of these proteins may lead to the development of nervous system malignancies and that these proteins may function as tumor suppressors. The mechanism of action of SOCS and VHL involved in neuronal differentiation and nervous system development is thought to be mediated through the inhibition of downstream signaling pathways, JAK-STAT, and hypoxia-inducible factor–vascular endothelial growth factor pathways. In addition, because SOCS and VHL promote nerve regeneration, they are expected to be applied in neuronal regenerative medicine for traumatic brain injury and stroke.

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“…Adult neurogenesis mainly occurs in the subgranular zone of the dentate gyrus of the hippocampus and the subventricular zone (SVZ) adjacent to the lateral ventricle [10,11]. Enhanced neurogenesis was found in hypoxic NSCs in vitro [12,13] and in ischemic brains of neonatal mice [14], adult rats [15] and aged humans in vivo [16]. Enhanced neurogenesis either by stem cell transplantation or stimulation of endogenous neurogenesis could partly amend the damaged brain functions, raising hopes for brain repair treatment.…”

Section: Introductionmentioning

confidence: 99%

Targeting Neurogenesis: A Promising Therapeutic Strategy for Post-Stroke Treatment with Chinese Herbal Medicine

Shen¹,

Chen²,

Chen³

et al. 2014

Integr Med Int

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Recent progress suggests that neural stem/progenitor cells can potentially develop into new functional neurons in adult brain, offering hope for regeneration therapies for stroke treatment. Targeting adult neurogenesis becomes a novel and promising therapeutic strategy for brain repair and recovery of neurological functions. Traditional Chinese Medicine (TCM) has a long history with accumulated experiences and case reports using herbal formulas to treat stroke disability. The combination of Chinese herbal medicine and stem cell biology approaches provides great potential for post-stroke rehabilitations. In the last decade, large efforts have been made to investigate the molecular targets for the regulation of adult neurogenesis and to explore the active compounds and molecular targets of herbal medicine for regeneration therapy. Herein, we reviewed the current progress concerning the molecular targets and cellular signaling pathways involved in adult neurogenesis after cerebral ischemia. We then briefly introduced Chinese medical theory and herbs for stroke treatment in TCM. Finally, we reviewed the current knowledge about the effects of Chinese herbal formulas, active fractions and active compounds on promoting adult neurogenesis as well as their molecular targets. Although the precise mechanisms and molecular targets of herbal medicine for neurogenesis are still unclear, current progress at least provides a cue for exploring the therapeutic principles of Chinese herbal medicine and developing new drugs for brain repair after stroke.

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The role of von Hippel–Lindau protein in the differentiation of neural progenitor cells under normoxic and anoxic conditions

Cited by 8 publications

References 12 publications

Caveolin-1 Plays a Crucial Role in Inhibiting Neuronal Differentiation of Neural Stem/Progenitor Cells via VEGF Signaling-Dependent Pathway

Caveolin-1 Plays a Crucial Role in Inhibiting Neuronal Differentiation of Neural Stem/Progenitor Cells via VEGF Signaling-Dependent Pathway

Role of SOCS and VHL Proteins in Neuronal Differentiation and Development

Targeting Neurogenesis: A Promising Therapeutic Strategy for Post-Stroke Treatment with Chinese Herbal Medicine

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