Transforming Growth Factor-βs Are Essential for the Development of Midbrain Dopaminergic Neurons<i>In Vitro</i>and<i>In Vivo</i>

Farkas, Lilla M.; Dünker, Nicole; Roussa, Eleni; Unsicker, Klaus; Krieglstein, Kerstin

doi:10.1523/jneurosci.23-12-05178.2003

Cited by 161 publications

(145 citation statements)

References 57 publications

Supporting

Mentioning

129

Contrasting

Unclassified

Order By: Relevance

“…After the next passage (passage 2) cells were grown in SHH and FGF8 for an additional week before differentiation in N2 medium supplemented with glial cell line-derived neuro- trophic factor, dibutyryl cAMP, and transforming growth factor type ␤3 [previously found to enhance En1 expression in the developing rodent midbrain (26)]. After differentiation of passage 2 cells (50 days in culture) 30-50% of the total cells derived from H1, H9, or HES-3 ( Fig.…”

Section: Patterning and Differentiation Of Neural Precursors From Es-mentioning

confidence: 99%

Derivation of midbrain dopamine neurons from human embryonic stem cells

Perrier

Tabar²,

Barberi³

et al. 2004

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

910

786

View full text Add to dashboard Cite

Human embryonic stem (hES) cells are defined by their extensive self-renewal capacity and their potential to differentiate into any cell type of the human body. The challenge in using hES cells for developmental biology and regenerative medicine has been to direct the wide differentiation potential toward the derivation of a specific cell fate. Within the nervous system, hES cells have been shown to differentiate in vitro into neural progenitor cells, neurons, and astrocytes. However, to our knowledge, the selective derivation of any given neuron subtype has not yet been demonstrated. Here, we describe conditions to direct hES cells into neurons of midbrain dopaminergic identity. Neuroectodermal differentiation was triggered on stromal feeder cells followed by regional specification by means of the sequential application of defined patterning molecules that direct in vivo midbrain development. Progression toward a midbrain dopamine (DA) neuron fate was monitored by the sequential expression of key transcription factors, including Pax2, Pax5, and engrailed-1 (En1), measurements of DA release, the presence of tetrodotoxin-sensitive action potentials, and the electron-microscopic visualization of tyrosinehydroxylase-positive synaptic terminals. High-yield DA neuron derivation was confirmed from three independent hES and two monkey embryonic stem cell lines. The availability of unlimited numbers of midbrain DA neurons is a first step toward exploring the potential of hES cells in preclinical models of Parkinson's disease. This experimental system also provides a powerful tool to probe the molecular mechanisms that control the development and function of human midbrain DA neurons.T he isolation of human embryonic stem (hES) cells (1) has stimulated research aimed at the selective generation of specific cell types for regenerative medicine. Although protocols have been developed for the directed differentiation of mouse embryonic stem (ES) cells into therapeutically relevant cell types, such as dopamine (DA) neurons (2, 3), motor neurons (4), and oligodendrocytes (5), the efficient generation of these cell types from hES cells has not yet been reported (6). Earlier studies demonstrating efficient neural differentiation from hES cells (7, 8) have yielded largely ␥-aminobutyric acid (GABA)ergic and glutamatergic neurons with a maximum of 3% DA neurons reported (9). A very recent study (10) reported up to 20% tyrosine hydroxylase (TH)-positive cells from hES cells but did not confirm midbrain DA neuron identity. A bias toward the generation of GABAergic and glutamatergic neurons is also observed in primary rodent and human neural precursor cells isolated from the CNS after expansion in the presence of epidermal growth factor and fibroblast growth factor (FGF). Similar to the work with primary neural precursors, current hES differentiation protocols require expansion of ES-derived neural precursors in FGF2. We have recently shown that extended FGF2 expansion of mouse ES-derived neural precursors selects for forebrain fate...

show abstract

Section: Patterning and Differentiation Of Neural Precursors From Es-mentioning

confidence: 99%

Derivation of midbrain dopamine neurons from human embryonic stem cells

Perrier

Tabar²,

Barberi³

et al. 2004

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

910

786

View full text Add to dashboard Cite

show abstract

“…TGF-b and Shh cooperatively induce DNs from ventral midbrain floor cells in vitro and in chick embryo in vivo Farkas et al 2003;, whereas Tgfb2 2/ ; Tgfb3 2/2 mice have a severe reduction in DNs at E14.5 (Roussa et al 2006). Glialderived neurotrophic factor (GDNF) promotes survival of embryonic DNs and inhibits the apoptotic death in postnatal midbrain DNs in vitro (Apostolides et al 1998;Burke 2003).…”

Section: Midbrainmentioning

confidence: 99%

“…Cite this article as Cold Spring Harb Perspect Biol 2017;9:a022244 entiation (Jordan et al 1997;Farkas et al 2003). BMP-7 induces dopamine neuron differentiation in culture, and promotes survival in the adult nigrostriatal pathway against dopamine toxins in vivo (Lee et al 2003;Harvey et al 2004;Chou et al 2008).…”

Section: Tgf-b and Neural Developmentmentioning

confidence: 99%

TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function

Meyers

Kessler

2017

Cold Spring Harb Perspect Biol

137

107

View full text Add to dashboard Cite

“…These include brain-derived neurotrophic factor 5 , neurotrophin-4 (ref. 6), glial cell line-derived neurotrophic factor (GDNF) 7 and TGFβ 8,9 . Most of these trophic factors have well-documented functions in regulating the survival of sensory, sympathetic and parasympathetic neurons during neurogenesis 10,11 , which raises the possibility that they may also provide survival cues to DA neurons during development 4,12 and thereby control the final number of DA neurons.…”

mentioning

confidence: 99%

“…One potential candidate for a pro-survival trophic factor is TGFβ, which promotes the survival of cultured DA neurons with a higher potency than GDNF 8,9,18 . Like GDNF, at least two TGFβ isoforms, TGFβ2 and TGFβ3, are expressed in the target tissues or in the vicinity of the midbrain DA neurons during development 19,20 .…”

mentioning

confidence: 99%

Essential function of HIPK2 in TGFβ-dependent survival of midbrain dopamine neurons

et al. 2006

View full text Add to dashboard Cite

Transforming growth factor beta (TGFβ) is a potent trophic factor for midbrain dopamine (DA) neurons, but its in vivo function and signaling mechanisms are not entirely understood. We show that the transcriptional cofactor homeodomain interacting protein kinase 2 (HIPK2) is required for the TGFβ-mediated survival of mouse DA neurons. The targeted deletion of Hipk2 has no deleterious effect on the neurogenesis of DA neurons, but leads to a selective loss of these neurons that is due to increased apoptosis during programmed cell death. As a consequence, Hipk2 −/− mutants show an array of psychomotor abnormalities. The function of HIPK2 depends on its interaction with receptor-regulated Smads to activate TGFβ target genes. In support of this notion, DA neurons from Hipk2 −/− mutants fail to survive in the presence of TGFβ3 and Tgfβ3 −/− mutants show DA neuron abnormalities similar to those seen in Hipk2 −/− mutants. These data underscore the importance of the TGFβ-Smad-HIPK2 pathway in the survival of DA neurons and its potential as a therapeutic target for promoting DA neuron survival during neurodegeneration.Ventral midbrain DA neurons in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) control extrapyramidal movement and a variety of cognitive

show abstract

Transforming Growth Factor-βs Are Essential for the Development of Midbrain Dopaminergic NeuronsIn VitroandIn Vivo

Cited by 161 publications

References 57 publications

Derivation of midbrain dopamine neurons from human embryonic stem cells

Derivation of midbrain dopamine neurons from human embryonic stem cells

TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function

Essential function of HIPK2 in TGFβ-dependent survival of midbrain dopamine neurons

Contact Info

Product

Resources

About