HB-GAM inhibits proliferation and enhances differentiation of neural stem cells

Hienola, Anni; Pekkanen, Mari; Raulo, Erkki; Vanttola, Päivi; Rauvala, Heikki

doi:10.1016/j.mcn.2004.01.018

Cited by 72 publications

(59 citation statements)

References 62 publications

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“…Although several reports have suggested an involvement of Brd2 in the process of neuronal differentiation (Gyuris et al, 2009;Tsume et al, 2012;Velíšek et al, 2011), specific conditional knockout mice are required to accurately assess this issue. Finally, despite functional redundancy between Ptn and Mdk, an interesting developmental phenotype associated with the single Ptn mutation in mice supports our model: absence of Ptn results in prolonged proliferation and therefore in impaired neurogenesis in the cerebral cortex (Hienola et al, 2004). Similarly, we have shown that Ptn knockdown in P19 cells impairs induced neuronal differentiation.…”

Section: Discussionsupporting

confidence: 82%

Pleiotrophin antagonizes Bromodomain-containing protein 2 (Brd2) during neuronal differentiation

García-Gutiérrez¹,

Juárez-Vicente²,

Wolgemuth³

et al. 2014

Journal of Cell Science

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Bromodomain-containing protein 2 (Brd2) is a BET family chromatin adaptor required for expression of cell-cycle-associated genes and therefore involved in cell cycle progression. Brd2 is expressed in proliferating neuronal progenitors, displays cell-cycle-stimulating activity and, when overexpressed, impairs neuronal differentiation. Paradoxically, Brd2 is also detected in differentiating neurons. To shed light on the role of Brd2 in the transition from cell proliferation to differentiation, we had previously looked for proteins that interacted with Brd2 upon induction of neuronal differentiation. Surprisingly, we identified the growth factor pleiotrophin (Ptn). Here, we show that Ptn antagonized the cell-cycle-stimulating activity associated with Brd2, thus enhancing induced neuronal differentiation. Moreover, Ptn knockdown reduced neuronal differentiation. We analyzed Ptnmediated antagonism of Brd2 in a cell differentiation model and in two embryonic processes associated with the neural tube: spinal cord neurogenesis and neural crest migration. Finally, we investigated the mechanisms of Ptn-mediated antagonism and determined that Ptn destabilizes the association of Brd2 with chromatin. Thus, Ptnmediated Brd2 antagonism emerges as a modulation system accounting for the balance between cell proliferation and differentiation in the vertebrate nervous system.

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Section: Discussionsupporting

confidence: 82%

Pleiotrophin antagonizes Bromodomain-containing protein 2 (Brd2) during neuronal differentiation

García-Gutiérrez¹,

Juárez-Vicente²,

Wolgemuth³

et al. 2014

Journal of Cell Science

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“…We have listed Ptn as a neuronal marker as it is expressed in specific areas of the developing and adult nervous system (49), Ptn-deficient mice exhibit neurophysiologic and behavioral phenotypes (50,51), and it is thought to affect the proliferation and differentiation of particular neuronal cell types (52,53). However, Ptn has also been proposed to play important roles in bone physiology, specifically as a positive regulator of both osteoblast differentiation and function (54,55).…”

Section: Discussionmentioning

confidence: 99%

Dominant-Stable β-Catenin Expression Causes Cell Fate Alterations and Wnt Signaling Antagonist Expression in a Murine Granulosa Cell Tumor Model

Boerboom¹,

White

Dalle

et al. 2006

Cancer Research

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Wnt/B-catenin signaling is normally involved in embryonic development and tissue homeostasis, and its misregulation leads to several forms of cancer. We have reported that misregulated Wnt/B-catenin signaling occurs in ovarian granulosa cell tumors (GCT) and have created the Catnb flox(ex3)/+ ; Amhr2 cre/+ mouse model, which expresses a dominant-stable mutant of B-catenin in granulosa cells and develops late-onset GCT. To study the mechanisms leading to GCT development, gene expression analysis was done using microarrays comparing Catnb flox(ex3)/+ ; Amhr2 cre/+ ovaries bearing pretumoral lesions with control ovaries. Overexpressed genes identified in Catnb flox(ex3)/+ ; Amhr2 cre/+ ovaries included the Wnt/B-catenin signaling antagonists Wif1, Nkd1, Dkk4, and Axin2, consistent with the induction of negative feedback loops that counteract uncontrolled Wnt/B-catenin signaling. Expression of the antagonists was localized to cells forming the pretumoral lesions but not to normal granulosa cells. Microarray analyses also revealed the ectopic expression of bone markers, including Ibsp, Cdkn1c, Bmp4, and Tnfrsf11b, as well as neuronal/neurosecretory cell markers, such as Cck, Amph, Pitx1, and Sp5. Increased expression of the gene encoding the cytokine pleiotrophin was also found in Catnb flox(ex3)/+ ; Amhr2 cre/+ ovaries and GCT but was not associated with increased serum pleiotrophin levels. In situ hybridization analyses using GCT from Catnb flox(ex3)/+ ; Amhr2 cre/+ mice revealed that Wnt/B-catenin antagonists and neuronal markers localized to a particular cell population, whereas the bone markers localized to a distinct cell type associated with areas of osseous metaplasia. Together, these results suggest that misregulated Wnt/B-catenin signaling alters the fate of granulosa cells and that the GCT that arise in Catnb flox(ex3)/+ ; Amhr2 cre/+ mice result from the clonal expansion of metaplastic cells. (Cancer Res 2006; 66(4): 1964-73)

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“…The number of BrdU-nestin double-positive cells in the developing rat brain was determined using unbiased stereology methods and the Stereo Investigator (MicroBrightField, Magdeburg, Germany) platform attached to an Olympus Optical (Tokyo, Japan) BX51 microscope. Cells were counted using the optical fractionator method in combination with the dissector principle and unbiased counting rules (Mouton et al, 2002;Hienola et al, 2004). The method was optimized to give a coefficient of error Ͻ8% per individual brain sample.…”

Section: Methodsmentioning

confidence: 99%

Glucocorticoid Hormones Decrease Proliferation of Embryonic Neural Stem Cells through Ubiquitin-Mediated Degradation of Cyclin D1

Sundberg¹,

Savola²,

Hienola³

et al. 2006

J. Neurosci.

105

102

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HB-GAM inhibits proliferation and enhances differentiation of neural stem cells

Cited by 72 publications

References 62 publications

Pleiotrophin antagonizes Bromodomain-containing protein 2 (Brd2) during neuronal differentiation

Pleiotrophin antagonizes Bromodomain-containing protein 2 (Brd2) during neuronal differentiation

Dominant-Stable β-Catenin Expression Causes Cell Fate Alterations and Wnt Signaling Antagonist Expression in a Murine Granulosa Cell Tumor Model

Glucocorticoid Hormones Decrease Proliferation of Embryonic Neural Stem Cells through Ubiquitin-Mediated Degradation of Cyclin D1

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