Fibroblast Growth Factor Receptors Cooperate to Regulate Neural Progenitor Properties in the Developing Midbrain and Hindbrain

Saarimäki-Vire, Jonna; Peltopuro, Paula; Lahti, Laura; Naserke, Thorsten; Blak, Alexandra; Weisenhorn, Daniela M. Vogt; Yu, Kai; Ornitz, David M.; Wurst, Wolfgang; Partanen, Juha

doi:10.1523/jneurosci.0192-07.2007

Cited by 85 publications

(77 citation statements)

References 42 publications

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“…In our purified mDA NPs study, we clearly observed that bFGF could remarkably support proliferation of mDA NP on its own. We also noted that FGF8 could support proliferation of mDA NPs, which is in agreement with previous studies (13). Interestingly, FGF20, which is implicated in mDA survival (19), did not support proliferation of mDA NPs, showing specificity among FGF family members in supporting mDA NP proliferation.…”

Section: Discussionsupporting

confidence: 92%

“…We next investigated the self-renewability (or expandability) of Otx2 + Corin + cells in response to various signaling molecules. We tested those factors implicated in the regulation of mDA NPs (e.g., Shh, FGF8, Wnt1, and Wnt5a) (2,(10)(11)(12)(13)(14) or the proliferation of general NPs (e.g., bFGF, EGF, Dll4, and Jag1) (15-18) as well as FGF20, which was implicated in mDA survival (19). Each factor was added for a week to mitogen-free media (ND media), which by itself does not support the proliferation of purified cells.…”

Section: Results Mda Nps Can Be Identified By Coexpression Of Otx2 Anmentioning

confidence: 99%

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ES cell-derived renewable and functional midbrain dopaminergic progenitors

Chung

Moon

Leung

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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During early development, midbrain dopaminergic (mDA) neuronal progenitors (NPs) arise from the ventral mesencephalic area by the combined actions of secreted factors and their downstream transcription factors. These mDA NPs proliferate, migrate to their final destinations, and develop into mature mDA neurons in the substantia nigra and the ventral tegmental area. Here, we show that such authentic mDA NPs can be efficiently isolated from differentiated ES cells (ESCs) using a FACS method combining two markers, Otx2 and Corin. Purified Otx2 + Corin + cells coexpressed other mDA NP markers, including FoxA2, Lmx1b, and Glast. Using optimized culture conditions, these mDA NPs continuously proliferated up to 4 wk with almost 1,000-fold expansion without significant changes in their phenotype. Furthermore, upon differentiation, Otx2 + Corin + cells efficiently generated mDA neurons, as evidenced by coexpression of mDA neuronal markers (e.g., TH, Pitx3, Nurr1, and Lmx1b) and physiological functions (e.g., efficient DA secretion and uptake). Notably, these mDA NPs differentiated into a relatively homogenous DA population with few serotonergic neurons. When transplanted into PD model animals, aphakia mice, and 6-OHDA-lesioned rats, mDA NPs differentiated into mDA neurons in vivo and generated well-integrated DA grafts, resulting in significant improvement in motor dysfunctions without tumor formation. Furthermore, grafted Otx2 + Corin + cells exhibited significant migratory function in the host striatum, reaching >3.3 mm length in the entire striatum. We propose that functional and expandable mDA NPs can be efficiently isolated by this unique strategy and will serve as useful tools in regenerative medicine, bioassay, and drug screening.neural precursors | dopaminergic neurons | transplantation

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Section: Discussionsupporting

confidence: 92%

Section: Results Mda Nps Can Be Identified By Coexpression Of Otx2 Anmentioning

confidence: 99%

ES cell-derived renewable and functional midbrain dopaminergic progenitors

Chung

Moon

Leung

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…The wnt family interacts with a set of receptors encoded by the fzd genes [49,86], with signals transduced by the dvl group and negatively modulated by the dkk genes [37]. Importantly for our work, the fgf and wnt families are coexpressed in adjacent locations within the developing brain and deletion of genes from either group produces parallel defects in forebrain development [9,38,66,69,70,100]. As in our earlier work [79], we utilized microarrays to examine the key members of each gene family, comparing similarities and differences in the effects of chlorpyrifos and diazinon: if the involvement of neurotrophic mechanisms is unrelated to the inhibition of cholinesterase, then there are likely to be significant disparities between the two agents.…”

Section: Introductionmentioning

confidence: 83%

Targeting of neurotrophic factors, their receptors, and signaling pathways in the developmental neurotoxicity of organophosphates in vivo and in vitro

Slotkin¹,

Seidler²,

Fumagalli³

2008

Brain Research Bulletin

127

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Neurotrophic factors control neural cell differentiation and assembly of neural circuits. We previously showed that organophosphate pesticides differentially regulate members of the fibroblast growth factor (fgf) gene family. We administered chlorpyrifos and diazinon to neonatal rats on postnatal days 1-4 at doses devoid of systemic toxicity or growth impairment, and spanning the threshold for barely-detectable cholinesterase inhibition. We evaluated the impact on gene families for different classes of neurotrophic factors. Using microarrays, we examined the regional expression of mRNAs encoding the neurotrophins (ntfs), brain-derived neurotrophic factor (bdnf), nerve growth factor (ngf), the wnt and fzd gene families and the corresponding receptors. Chlorpyrifos and diazinon both had widespread effects on the fgf, ntf, wnt and fzd families but much less on the bdnf and ngf groups. However, the two organophosphates showed disparate effects on a number of key neurotrophic factors. To determine if the actions were mediated directly on differentiating neurons, we tested chlorpyrifos in PC12 cells, an in vitro model of neural cell development. Effects in PC12 cells mirrored many of those for members of the fgf, ntf and wnt families, as well as the receptors for the ntfs, especially during early differentiation, the stage known to be most susceptible to disruption by organophosphates. Our results suggest that actions on neurotrophic factors provide a mechanism for the developmental neurotoxicity of low doses of organophosphates, and, since effects on expression of the affected genes differed with test agent, may help explain regional disparities in effects and critical periods of vulnerability.

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“…However, relatively little is known about FGFR 2 distribution in the CNS. Previous studies provide conflicting evidence (Pettmann et al, 1986;Finklestein et al, 1988;Grothe et al, 1991;Yamamoto et al, 1991;Gomez-Pinilla et al, 1992;Matsuda et al, 1992;Matsuyama et al, 1992;Woodward et al, 1992;Eckenstein et al, 1994) or are limited to specific areas of the brain Frautschy et al, 1991;Matsuda et al, 1992;1993;Stock et al, 1992;Tooyama et al, 1992;Tooyama et al, 1993a;1993b;Gonzalez et al, 1994;Saarimaki-Vire et al, 2007).…”

Section: Ajnmentioning

confidence: 99%

SPATIAL DISTRIBUTION OF FIBROBLAST GROWTH FACTOR RECEPTOR 2 IN NORMAL AND LESIONED CENTRAL NERVOUS SYSTEM OF <I>PLEURODELES WALTLII</I>

Moftah

Landry

Nagy

et al. 2012

American Journal of Neuroscience

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Fibroblast Growth Factors (FGFs) have been implicated in numerous cellular processes including proliferation, migration, differentiation and neuronal survival. One of these growth factors, Fibroblast Growth Factor 2 (FGF2), is apparently implicated in the ability of the adult salamander (Pleurodeles waltlii) to recover locomotion following complete transection of the spinal cord. In a previous study, we reported up regulation of FGF2 during regeneration of damaged axons and recovery of hind limb locomotion. In this study reported here, we investigated the spatial distribution of FGFR2-one of the receptors that mediate the effects of FGF2-using a variety of techniques, namely, western blot, immunohistochemistry and in situ hybridization. We find that in intact animals FGFR2 is mainly expressed in the most posterior part of body Spinal Cord (SC3) specifically in neurons. However, lesioning the spinal cord produces increased expression in Brainstem (BS) neurons and decreased expression in posterior parts of the spinal cord not only in neurons but also in the neuroglial ependymal cells lining the central canal. This suggests that FGF2 simultaneously activates FGFR1 and 2, perhaps at different points in the regeneration process and thus FGFR2 might play at least an indirect role in the spontaneous regeneration observed in this species and might be relevant to the treatment of spinal cord lesions in humans. Verification of this possibility will require studies of additional time points.

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Fibroblast Growth Factor Receptors Cooperate to Regulate Neural Progenitor Properties in the Developing Midbrain and Hindbrain

Cited by 85 publications

References 42 publications

ES cell-derived renewable and functional midbrain dopaminergic progenitors

ES cell-derived renewable and functional midbrain dopaminergic progenitors

Targeting of neurotrophic factors, their receptors, and signaling pathways in the developmental neurotoxicity of organophosphates in vivo and in vitro

SPATIAL DISTRIBUTION OF FIBROBLAST GROWTH FACTOR RECEPTOR 2 IN NORMAL AND LESIONED CENTRAL NERVOUS SYSTEM OF <I>PLEURODELES WALTLII</I>

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