Sonic hedgehog induces the differentiation of ventral forebrain neurons: A common signal for ventral patterning within the neural tube

Ericson, Johan; Muhr, Jonas; Placzek, Marysia; Lints, Thierry; Jessel, T.M; Edlund, Thomas

doi:10.1016/0092-8674(95)90536-7

Cited by 521 publications

(322 citation statements)

References 47 publications

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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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“…Regarding other potential mediators of the transcription factors' influences on angiogenesis, it is well known that sonic hedgehog (Shh) induces Nkx2.1 expression 35,36 and that Shh has pivotal roles in both neurogenesis and angiogenesis 37 . In Nkx2.1 −/− mutants, at E10.5 and E11.5, Shh expression is virtually undetectable in the basal telencephalon 12 .…”

Section: Compartmental Influences On Telencephalic Angiogenesismentioning

confidence: 99%

Compartment-specific transcription factors orchestrate angiogenesis gradients in the embryonic brain

et al. 2008

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Prevailing notions of cerebral vascularization imply that blood vessels sprout passively into the brain parenchyma from pial vascular plexuses to meet metabolic needs of growing neuronal populations. Endothelial cells, building blocks of blood vessels, are thought to be homogeneous in the brain with respect to their origins, gene expression patterns and developmental mechanisms. These current notions that cerebral angiogenesis is regulated by local environmental signals contrast with current models of cell-autonomous regulation of neuronal development. Here we demonstrate that telencephalic angiogenesis in mice progresses in an orderly, ventral-to-dorsal gradient regulated by compartment-specific homeobox transcription factors. Our data offer new perspectives on intrinsic regulation of angiogenesis in the embryonic telencephalon, call for a revision of the current models of telencephalic angiogenesis and support novel roles for endothelial cells in brain development.Brain development is supported by concomitant development of brain vasculature. However, blood vessels or endothelial cells are generally considered to lack molecular diversity in the embryonic or mature CNS 1,2 . Currently, it is believed that once the perineural plexuses on the pial surface (pial vessels) surrounding the neural tube are produced, cerebral vasculature develops further by passive vessel sprouting into the brain parenchyma in response to increased tissue mass and oxygen demand 1,2 . Although classical studies identified a ventral to dorsal temporal developmental angiogenesis gradient in the telencephalon 3 , the sequence of angiogenesis was considered to merely shadow neurogenesis and neuronal maturation. Similarly, although shared mechanisms regulating vascular and neuronal development have been recognized 4 , the canonical principles of neuronal development are not seen as applicable to CNS angiogenesis.

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“…Because vertebrate and Drosophila eye development appear to require many of the same transcription factors, it is plausible that they would require some of the same cell-signaling molecules (for review, see Reh and Cagan, 1994). Second, in vertebrates, members of the Hedgehog family have been shown to act as inducing molecules for particular cell fates in spinal cord and mesencephalon (Roelink et al, 1994;Ericson et al, 1995;Hynes et al, 1995), and it is likely that these molecules play important roles in the overall patterning of the developing nervous system (Ekker et al, 1995b). Third, in vertebrates, Sonic hedgehog (Shh) expression in the zone of polarizing activity can be induced by retinoic acid (RA) (for review, see Johnson and Tabin, 1995), and recently we have reported that RA can act as a rod photoreceptor inducer in embryonic rat retinal cell cultures (Kelley et al, 1994.…”

Section: Abstract: Sonic Hedgehog; Indian Hedgehog; Desert Hedgehog;mentioning

confidence: 99%

Sonic Hedgehog Promotes Rod Photoreceptor Differentiation in Mammalian Retinal CellsIn Vitro

et al. 1997

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The hedgehog gene family encodes secreted proteins important in many developmental patterning events in both vertebrates and invertebrates. In the Drosophila eye disk, hedgehog controls the progression of photoreceptor differentiation in the morphogenetic furrow. To investigate whether hedgehog proteins are also involved in the development of the vertebrate retina at stages of photoreceptor differentiation, we analyzed expression of the three known vertebrate hedgehog genes. We found that Sonic hedgehog and Desert hedgehog are expressed in the developing retina, albeit at very low levels, whereas Indian hedgehog (Ihh) is expressed in the developing and mature retinal pigmented epithelium, beginning at embryonic day 13. To determine whether hedgehog proteins have activities on developing retinal cells, we used an in vitro system in which much of retinal histogenesis is recapitulated. N-terminal recombinant Sonic Hedgehog protein (SHH-N) was added to rat retinal cultures for 3-12 d, and the numbers of retinal cells of various phenotypes were analyzed by immunohistochemistry. We found that SHH-N caused a transient increase in the number of retinal progenitor cells, and a 2-to 10-fold increase in the number of photoreceptors differentiating in the cultures when analyzed with three different photoreceptor-specific antigens. In contrast, the numbers of retinal ganglion cells and amacrine cells were similar to those in control cultures. These results show that Hedgehog proteins can regulate mitogenesis and photoreceptor differentiation in the vertebrate retina, and Ihh is a candidate factor from the pigmented epithelium to promote retinal progenitor proliferation and photoreceptor differentiation.

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Sonic hedgehog induces the differentiation of ventral forebrain neurons: A common signal for ventral patterning within the neural tube

Cited by 521 publications

References 47 publications

Dopaminergic Differentiation of Human Embryonic Stem Cells

Dopaminergic Differentiation of Human Embryonic Stem Cells

Compartment-specific transcription factors orchestrate angiogenesis gradients in the embryonic brain

Sonic Hedgehog Promotes Rod Photoreceptor Differentiation in Mammalian Retinal CellsIn Vitro

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