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Extracellular signal-regulated protein kinase signaling is uncoupled from initial differentiation of central nervous system stem cells to neurons
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
2002 (English)In: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 1, no 2, 147-154 p.Article in journal (Refereed) Published
Abstract [en]

Knowledge about signaling pathways in response to external signals is needed to understand the regulation of stem cell proliferation and differentiation toward particular cell fates. The Ras/extracellular signal-regulated kinase (ERK) pathway has been suggested to play an essential role in neuronal differentiation. We have examined ERK signaling in the transition from multipotent stem cell to post-mitotic progeny using primary stem cells from the rat embryonic cortex. Fibroblast growth factor-2 (FGF-2) is a stem cell mitogen, whereas platelet-derived growth factor AA (PDGF-AA) expands a pool of committed neuronal precursors from stem cells. When comparing ERK activation by these growth factors, we found that FGF-2 stimulates high and PDGF-AA lower levels of ERK phosphorylation in stem cells. Differentiation was monitored as down-regulation of the bHLH transcription factor mammalian achaete-scute homologue-1 (MASH1). Even in the absence of active ERK, MASH1 became down-regulated and microtubule-associated protein 2-positive cells could form. Thus, ERK activation seems dispensable for the earliest steps of CNS stem cell differentiation.

Place, publisher, year, edition, pages
2002. Vol. 1, no 2, 147-154 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-90758ISI: 000181772500007PubMedID: 12496361OAI: oai:DiVA.org:uu-90758DiVA: diva2:163221
Available from: 2003-09-11 Created: 2003-09-11 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Neural Stem Cell Differentiation and Migration
Open this publication in new window or tab >>Neural Stem Cell Differentiation and Migration
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neural stem cells are the precursors of neurons, astrocytes and oligodendrocytes. During neural development, the division of stem cells takes place close to the lumen of the neural tube, after which they migrate to their final positions within the central nervous system (CNS). Soluble factors, including growth factors, regulate neural stem cell proliferation, survival, migration and differentiation towards specific cell lineages.

This thesis describes the function of platelet-derived growth factor (PDGF) and stem cell factor (SCF) in neural stem cell regulation. PDGF was previously suggested to stimulate neuronal differentiation, but the mechanisms were not defined. This study shows that PDGF is a mitogen and a survival factor that expands a pool of immature cells from neural stem cells. The PDGF-treated cells can be stained by neuronal markers, but need further stimuli to continue their maturation. They can become either neurons or glia depending on the secondary instructive cues. Moreover, neural stem cells produce PDGF. Inhibition of this endogenous PDGF negatively affects the cell number in stem cell cultures. We find that SCF stimulates migration and supports the survival of neural stem cells, but that it has no effect on their proliferation or differentiation into neurons and glia. Intracellular signaling downstream from the receptors for PDGF and SCF includes activation of extracellular signal-regulated kinase (ERK). This investigation shows that active ERK is not needed for the differentiation of stem cells into neurons, at least not during early stages.

Neural stem cells have a future potential in the treatment of CNS disorders. To be able to use neural stem cells clinically we need to understand how their proliferation, differentiation, survival and migration are controlled. The results presented in this thesis increase our knowledge of how neural stem cells are regulated by growth factors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 73 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1281
Keyword
Medicine, CNS, stem cells, neuron, PDGF, SCF, differentiation, migration, ERK, Medicin
National Category
Dermatology and Venereal Diseases
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:uu:diva-3546 (URN)91-554-5714-2 (ISBN)
Public defence
2003-10-03, B21, BMC, Uppsala, 13:15
Opponent
Supervisors
Available from: 2003-09-11 Created: 2003-09-11 Last updated: 2016-04-29Bibliographically approved
2. Roles of PDGF for Neural Stem Cells
Open this publication in new window or tab >>Roles of PDGF for Neural Stem Cells
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Stem cells are endowed with unique qualities: they can both self-renew and give rise to new mature cell types. Central nervous system (CNS) stem cells can give rise to neurons and glia. What factors regulate stem cell fate decisions? Identifying signals that are involved in the regulation of CNS stem cell proliferation, survival, differentiation and migration is fundamental to the understanding of CNS development. In addition, this knowledge hopefully will contribute to more efficient therapies of CNS damages and diseases.

The focus of this thesis was to investigate mechanisms of CNS stem cell proliferation and differentiation. We have studied the role for platelet-derived growth factor (PDGF) in these cellular events both in vitro and in vivo. Previous reports have shown that PDGF are implicated in brain tumorigenesis and also supports neuronal differentiation of CNS stem cells. We have found that PDGF promotes survival and proliferation of immature neurons, thereby supporting neuronal differentiation. The intracellular Ras/ERK signaling pathway probably mediates the mitogenic activity of PDGF. In contrast, neuronal differentiation is not dependent on the Ras/ERK pathway. A genetic expression profile of stem cells during their differentiation was obtained. This microarray analysis suggests that PDGF-treated stem cells are at an intermediate stage between proliferation and differentiation. Furthermore, we generated transgenic mice that overexpress Pdgf-b in neural stem cells. Preliminary data indicate no signs of enhanced proliferation of immature neurons. Instead, increased apoptosis was detected in the developing striatum.

The results presented in this thesis show how CNS stem cells are regulated by PDGF. PDGFs are widely expressed in the developing CNS and also in some brain tumors, which are thought to arise from CNS stem cells. Thus, this knowledge may contribute to an increased understanding of brain tumorigenesis in addition to normal CNS development.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 60 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1348
Keyword
Developmental biology, CNS, stem cells, neuron, PDGF, proliferation, differentiation, ERK, microarray, transgenic mouse, Utvecklingsbiologi
National Category
Developmental Biology
Identifiers
urn:nbn:se:uu:diva-4245 (URN)91-554-5956-0 (ISBN)
Public defence
2004-05-19, B41, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2004-04-28 Created: 2004-04-28 Last updated: 2016-04-29Bibliographically approved

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Enarsson, MariaErlandsson, AnnaForsberg-Nilsson, Karin

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