FGF and Shh Signals Control Dopaminergic and Serotonergic Cell Fate in the Anterior Neural Plate

Ye, Weilan; Shimamura, Kenji; Rubenstein, John L.R.; Hynes, Mary; Rosenthal, Arnon

doi:10.1016/s0092-8674(00)81437-3

Cited by 792 publications

(629 citation statements)

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“…A second pathway involving Lmx1b and Ptx3 seems to be important for expression of other aspects of the dopaminergic neuronal phenotype [36]. Shh and FGF8 induce the dopaminergic phenotype when present in appropriate concentrations in specific brain regions [33,37,38]. The receptor for Shh is Smo, which is inhibited by a second protein patched (ptch) when Shh is absent [39][40][41].…”

Section: Discussionmentioning

confidence: 99%

Dopaminergic Differentiation of Human Embryonic Stem Cells

et al. 2004

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In this manuscript we report that human embryonic stem cells (hESCs) differentiated into dopaminergic neurons when cocultured with PA6 cells. After 3 weeks of differentiation, approximately 87% of hES colonies contained tyrosine hydroxylase (TH)–positive cells, and a high percentage of the cells in most of the colonies expressed TH. Differentiation was inhibited by exposure to BMP4 or serum. TH‐positive cells derived from hESCs were postmitotic, as determined by bromodeoxyurindine colabeling. Differentiated cells expressed other markers of dopaminergic neurons, including the dopamine transporter, aromatic amino acid decarboxylase, and the transcription factors associated with neuronal and dopaminergic differentiation, Sox1, Nurr1, Ptx3, and Lmx1b. Neurons that had been differentiated on PA6 cells were negative for dopamine‐β‐hydroxylase, a marker of noradrenergic neurons. PA6‐induced neurons were able to release dopamine and 3,4‐dihydroxphe‐hylacetic acid (DOPAC) but not noradrenalin when depolarized by high K+. When transplanted into 6‐hydroxydopamine–treated animals, hES‐derived dopaminergic cells integrated into the rat striatum. Five weeks after transplantation, surviving TH‐positive cells were present but in very small numbers compared with the high frequency of TH‐positive cells seen in PA6 coculture. Larger numbers of cells positive for smooth muscle actin, but no undifferentiated ES cells, were present after transplantation. Therefore, hESCs can be used to generate human dopaminergic cells that exhibit biochemical and functional properties consistent with the expected properties of mature dopaminergic neurons.

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Section: Discussionmentioning

confidence: 99%

Dopaminergic Differentiation of Human Embryonic Stem Cells

et al. 2004

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“…In contrast, 5% of the transcripts in the hypothalamic DA neurons differed from those of the SN or VTA neurons. DA neurons in the midbrain and hypothalamus each expressed specific sets of transcriptional regulators, suggesting that although both neuronal classes depend on Fgf8 and Shh for their early specification (42), their later phenotype is maintained, in part, by independent regulatory cascades. Such a cascade would include the DA midbrain-and forebrain-specific transcription factors PBX1, ZFH-4, IFI 116, Bteb2, Lmo2, Prox1, and Hnf-6 that have been identified here, as well as the known transcriptional regulators of DA differentiation and survival Nurr1, Lmx1b, and Pitx3.…”

Section: Discussionmentioning

confidence: 99%

Molecular basis for catecholaminergic neuron diversity

Grimm

Mueller

Hefti

et al. 2004

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

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133

141

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Catecholaminergic neurons control diverse cognitive, motor, and endocrine functions and are associated with multiple psychiatric and neurodegenerative disorders. We present global gene-expression profiles that define the four major classes of dopaminergic (DA) and noradrenergic neurons in the brain. Hypothalamic DA neurons and noradrenergic neurons in the locus coeruleus display distinct group-specific signatures of transporters, channels, transcription, plasticity, axon-guidance, and survival factors. In contrast, the transcriptomes of midbrain DA neurons of the substantia nigra and the ventral tegmental area are closely related with <1% of differentially expressed genes. Transcripts implicated in neural plasticity and survival are enriched in ventral tegmental area neurons, consistent with their role in schizophrenia and addiction and their decreased vulnerability in Parkinson's disease. The molecular profiles presented provide a basis for understanding the common and population-specific properties of catecholaminergic neurons and will facilitate the development of selective drugs.C atecholaminergic (CA) neurons producing the neurotransmitters dopamine (DA) and noradrenalin (NA) are organized in anatomically discrete groups and constitute Ϸ1 of 10 7 cells in the vertebrate CNS (1, 2). The most prominent groups of DA neurons reside in the substantia nigra (SN; A9 cell group; Ϸ10,000 neurons in the rat) and the ventral tegmental area (VTA; A10; Ϸ25,000 neurons) of the midbrain. The SN neurons provide the nigrostriatal ascending inputs to the telencephalon and comprise a key component of the extrapyramidal motor system controlling postural reflexes and initiation of movement. DA neurons in the adjacent VTA give rise to mesocortical and mesolimbic pathways that are implicated in control of emotional balance, reward-associated behavior, attention, and memory. Additional groups of DA neurons reside in the medial zona incerta of the hypothalamus (A13; Ϸ900 neurons) and participate in the regulation of endocrine functions. The largest collection of NA neurons resides in the pontine locus coeruleus (LC; Ϸ1,500 neurons). These neurons form a modulatory projection system to most CNS areas and contribute to the regulation of emotional status, sensory perception, arousal, sleepwake patterns, and most autonomic functions.Consistent with their varied functions, the CA neurons are associated with multiple neurodegenerative, psychiatric, and endocrine disorders. Selective degeneration of DA neurons in the SN but not in the VTA or the hypothalamus leads to Parkinson's disease (PD) (3-7), whereas abnormal function of the VTA DA neurons has been linked to schizophrenia, attention deficit, addiction, and hyperactivity disorders (8-11). In addition, dysfunction of hypothalamic DA neurons can cause hyperprolactinemia, an endocrine disorder of the reproductive system (12), whereas changes in the activity of the NA system have been linked to depression as well as sleep disorders (13,14).The drugs currently available for therapy reflec...

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“…Previous work identified SHH and FGF8 as crucial factors in the specification of midbrain DA neurons (24). These studies in explant culture and subsequent work with mouse ES cells (2,11,22) demonstrated that the effect of SHH and FGF8 on dopaminergic differentiation is limited to distinct developmental windows that correspond to the establishment of the isthmic organizer and events controlling dorsoventral patterning during neural tube closure.…”

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

confidence: 97%

Derivation of midbrain dopamine neurons from human embryonic stem cells

Perrier

Tabar²,

Barberi³

et al. 2004

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

906

786

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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...

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FGF and Shh Signals Control Dopaminergic and Serotonergic Cell Fate in the Anterior Neural Plate

Cited by 792 publications

References 55 publications

Dopaminergic Differentiation of Human Embryonic Stem Cells

Dopaminergic Differentiation of Human Embryonic Stem Cells

Molecular basis for catecholaminergic neuron diversity

Derivation of midbrain dopamine neurons from human embryonic stem cells

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