Vitronectin promotes the progress of the initial differentiation stage in cerebellar granule cells

Hashimoto, Kei; Sakane, Fumi; Ikeda, Natsumi; Akiyama, Ayumi; Sugahara, Miyaka; Miyamoto, Yasunori

doi:10.1016/j.mcn.2015.11.013

Cited by 16 publications

(8 citation statements)

References 31 publications

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“…In the CNS, the potential role for this interaction is less well documented. Both IGF and IGFBPs are present after TBI [1,2,4] and the differentiation of cerebellar granular cells [25] and motor neurons are dependent on vitronectin [24]. Our findings of vitronectin as favorable compared to the control (Figure 2 and Figure 4) was thus not unexpected.…”

Section: Discussionsupporting

confidence: 57%

“…Together with IGF-binding proteins (IBFBP), IGF-1 and vitronectin form a multiprotein complex which acts to coactivate the IGF-1 receptor [23]. Vitronectin has also in itself been attributed an important role in spinal motor neuron differentiation [24] as well as in the differentiation of cerebellar granular cells [25]. However, whether an interaction between IGF/IGFBP/vitronectin is important for neuronal polarity, survival, or regeneration in the CNS remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Neurite Growth and Polarization on Vitronectin Substrate after in Vitro Trauma is not Enhanced after IGF Treatment

et al. 2018

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Following traumatic brain injuries (TBI), insulin-like growth factor (IGF) is cortically widely upregulated. This upregulation has a potential role in the recovery of neuronal tissue, plasticity, and neurotrophic activity, though the molecular mechanisms involved in IGF regulation and the exact role of IGF after TBI remain unclear. Vitronectin (VN), an extracellular matrix (ECM) molecule, has recently been shown to be of importance for IGF-mediated cellular growth and migration. Since VN is downregulated after TBI, we hypothesized that insufficient VN levels after TBI impairs the potential beneficial activity of IGF. To test if vitronectin and IGF-1/IGFBP-2 could contribute to neurite growth, we cultured hippocampal neurons on ± vitronectin-coated coverslips and them treated with ± IGF-1/IGF binding protein 2 (IGFBP-2). Under same conditions, cell cultures were also subjected to in vitro trauma to investigate differences in the posttraumatic regenerative capacity with ± vitronectin-coated coverslips and with ± IGF-1/IGFBP-2 treatment. In both the control and trauma situations, hippocampal neurons showed a stronger growth pattern on vitronectin than on the control substrate. Surprisingly, the addition of IGF-1/IGFBP-2 showed a decrease in neurite growth. Since neurite growth was measured as the number of neurites per area, we hypothesized that IGF-1/IGFBP-2 contributes to the polarization of neurons and thus induced a less dense neurite network after IGF-1/IGFBP-2 treatment. This hypothesis could not be confirmed and we therefore conclude that vitronectin has a positive effect on neurite growth in vitro both under normal conditions and after trauma, but that addition of IGF-1/IGFBP-2 does not have a positive additive effect.

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Section: Discussionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Neurite Growth and Polarization on Vitronectin Substrate after in Vitro Trauma is not Enhanced after IGF Treatment

et al. 2018

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“…Interestingly, laminin is present only in the basement membrane surrounding the EGL that proliferating GNPs contact 5 , 6 . The laminin-rich ECM transitions to vitronectin deeper in the iEGL and ML 6 , 74 . We have provided data showing that vitronectin counters the mitogenic effect of Shh by blocking primary ciliogenesis in GNPs demonstrating an exquisite specificity of ECM to Shh coincidence detection: while both integrin β1 involved in laminin 75 binding and integrin β3 involved in vitronectin 76 binding both signal through the Ras–MAPK cascade only laminin supports Shh-induced ciliogenesis.…”

Section: Discussionmentioning

confidence: 99%

Siah2 integrates mitogenic and extracellular matrix signals linking neuronal progenitor ciliogenesis with germinal zone occupancy

et al. 2020

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Evidence is lacking as to how developing neurons integrate mitogenic signals with microenvironment cues to control proliferation and differentiation. We determine that the Siah2 E3 ubiquitin ligase functions in a coincidence detection circuit linking responses to the Shh mitogen and the extracellular matrix to control cerebellar granule neurons (CGN) GZ occupancy. We show that Shh signaling maintains Siah2 expression in CGN progenitors (GNPs) in a Ras/Mapk-dependent manner. Siah2 supports ciliogenesis in a feed-forward fashion by restraining cilium disassembly. Efforts to identify sources of the Ras/Mapk signaling led us to discover that GNPs respond to laminin, but not vitronectin, in the GZ microenvironment via integrin β1 receptors, which engages the Ras/Mapk cascade with Shh, and that this niche interaction is essential for promoting GNP ciliogenesis. As GNPs leave the GZ, differentiation is driven by changing extracellular cues that diminish Siah2-activity leading to primary cilia shortening and attenuation of the mitogenic response.

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“…VTN−/− mice have a subtle phenotype, including an increased rate of thrombosis after vascular injury and reduced angiogenesis after tissue injury (Eitzman et al, 2000;Jang et al, 2000). In the cerebellum of VTN−/− mice, the granule cell precursors have dysfunctional initial differentiation during development (Hashimoto et al, 2016). Little was known about the role of VTN in healthy adult tissues (Leavesley et al, 2013;Preissner and Reuning, 2011) and this study adds important new insight for its normal function in the brain and points to the potential to utilize its activities to regulate cytokine expression and increase neurogenesis.…”

Section: Discussionmentioning

confidence: 99%

Vitronectin from brain pericytes promotes adult forebrain neurogenesis by stimulating CNTF

Jia

Keasey

Malone

et al. 2019

Experimental Neurology

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Vitronectin (VTN) is a glycoprotein in the blood and affects hemostasis. VTN is also present in the extracellular matrix of various organs but little is known about its function in healthy adult tissues. We show, in adult mice, that VTN is uniquely expressed by approximately half of the pericytes of subventricular zone (SVZ) where neurogenesis continues throughout life. Intracerebral VTN antibody injection or VTN knockout reduced neurogenesis as well as expression of pro-neurogenic CNTF, and anti-neurogenic LIF and IL-6. Conversely, injections of VTN, or plasma from VTN+/+, but not VTN−/− mice, increased these cytokines. VTN promoted SVZ neurogenesis when LIF and IL-6 were suppressed by co-administration of a gp130 inhibitor. Unexpectedly, VTN inhibited FAK signaling and VTN−/− mice had increased FAK signaling in the SVZ. Further, an FAK inhibitor or VTN increased CNTF expression, but not in conditional astrocytic FAK knockout mice, suggesting that VTN increases CNTF through FAK inhibition in astrocytes. These results identify a novel role of pericyte-derived VTN in the brain, where it regulates SVZ neurogenesis through co-expression of CNTF, LIF and IL-6. VTN-integrin-FAK and gp130 signaling may provide novel targets to induce neurogenesis for cell replacement therapies.

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Vitronectin promotes the progress of the initial differentiation stage in cerebellar granule cells

Cited by 16 publications

References 31 publications

Neurite Growth and Polarization on Vitronectin Substrate after in Vitro Trauma is not Enhanced after IGF Treatment

Neurite Growth and Polarization on Vitronectin Substrate after in Vitro Trauma is not Enhanced after IGF Treatment

Siah2 integrates mitogenic and extracellular matrix signals linking neuronal progenitor ciliogenesis with germinal zone occupancy

Vitronectin from brain pericytes promotes adult forebrain neurogenesis by stimulating CNTF

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