A critical role for sonic hedgehog signaling in the early expansion of the developing brain

Britto, Joanne M.; Tannahill, David; Keynes, Roger J.

doi:10.1038/nn797

Cited by 111 publications

(95 citation statements)

References 45 publications

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“…Our present results taken together with previous studies Britto et al, 2002;Ishibashi and McMahon, 2002;Corrales et al, 2006) suggest several mechanisms by which Gli transcription factors regulate tissue growth. At high levels of signaling, Shh can simply increase proliferation by upregulating GliA (primarily Gli2) such as in cerebellar granule cell precursors , and/or by downregulating Gli3R such as in the ventral midbrain .…”

Section: Research Articlesupporting

confidence: 86%

Gli3 coordinates three-dimensional patterning and growth of the tectum and cerebellum by integrating Shh and Fgf8 signaling

2008

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The coordination of anterior-posterior (AP) and dorsal-ventral (DV) patterning of the mesencephalon (mes) and rhombomere 1 (r1) is instrumental for the development of three distinct brain structures: the tectum and cerebellum dorsally and the tegmentum ventrally. Patterning of the mes/r1 is primarily mediated by signaling molecules secreted from two organizers: sonic hedgehog (Shh) from the floor plate (DV) and Fgf8 from the isthmus (AP). Gli3, a zinc-finger transcription factor in the Shh signaling pathway, has been implicated in regulating Fgf8 expression and is therefore a potential candidate for coordinating the action of the two organizers. By inactivating mouse Gli3 at successive embryonic time points in vivo, we uncovered the extent and the underlying mechanism of Gli3 function in the mes/r1. We demonstrate that before E9.0, Gli3 is required for establishing a distinct posterior tectum, isthmus and cerebellum, but does not play a role in the development of the tegmentum. Between E9.0 and E11.0, Gli3 continues to be required for isthmus and cerebellum development, but primarily for defining the cerebellar foliation pattern. We show that Gli3 regulates patterning of the isthmus and cerebellar anlage by confining Fgf8 expression to the isthmus, and attenuates growth of dorsal r1 (before E11.0) and the dorsal mes and isthmus (beyond E11.0) through regulation of cell proliferation and viability. In conclusion, our results show that Gli3 is essential for the coordinated three-dimensional patterning and growth of the dorsal mes/r1. KEY WORDS: Anterior-posterior patterning, Dorsal-ventral patterning, Isthmic organizer, Mid/hindbrain, Mouse

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Section: Research Articlesupporting

confidence: 86%

Gli3 coordinates three-dimensional patterning and growth of the tectum and cerebellum by integrating Shh and Fgf8 signaling

2008

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“…In addition, Spence et al (personal communication) have shown that Shh expressing retrovirus stimulates retinal regeneration from the CMZ of embryonic chicks. Despite the large number of studies demonstrating a role for Shh in regulation of proliferation during embryogenesis in both mammals and birds (see for review, Britto et al, 2002), one previous report failed to observe a mitogenic effect of Shh using replication-competent retroviral vector-mediated Shh up-regulation in embryonic chick explant cultures (Zhang and Yang, 2001a). There is one possible explanation for the differences between their assay and ours: mitogenic effects of growth factors are diminished when assayed in explant cultures as opposed to dissociated cultures (Lillien and Cepko, 1992).…”

Section: Discussionmentioning

confidence: 99%

Sonic hedgehog regulates proliferation of the retinal ciliary marginal zone in posthatch chicks

2005

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The ciliary marginal zone (CMZ) has long been known to be a source of postembryonic neuronal production in the retinas of fish and amphibians, and more recently, birds. However, there is little known about the factors that are required for the maintenance of this neural stem cell zone. The cells of the CMZ respond to mitogens such as endothelial growth factor, insulin-like growth factor-1, and insulin, factors that are also mitogenic for embryonic retinal progenitors, suggesting that the continued expression of embryonic mitogenic factors might be required to maintain the postembryonic proliferative potential of the CMZ. To test this hypothesis, we examined the expression and functional role of a critical embryonic retinal progenitor mitogen, Sonic hedgehog (Shh) in the regulation of proliferation of the cells of the CMZ. We have found that Shh is concentrated at the retinal margin of postembryonic chicks. Moreover, we report that intraocular injection of Shh stimulates proliferation of the CMZ cells, whereas cyclopamine, an inhibitor of the Shh pathway, inhibits CMZ proliferation. We conclude that Shh signaling is an important factor in the maintenance of postembryonic retinal neurogenesis. Developmental Dynamics 233:66 -75, 2005.

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“…Shh loss of function through notochord resection or cyclopamine treatment results in a failure of this expansion in chick and quail embryos. 16 Notochord removal, eliminating Hh signaling, was also found to increase the time for cell cycle traversal. It was suggested that this reflected lengthening of M and G 1 phases.…”

Section: Hh Signaling In the Growth And Evolution Of The Nervous Systemmentioning

confidence: 96%

A General Role of Hedgehog in the Regulation of Proliferation

Agathocleous¹,

Locker²,

Harris³

et al. 2007

Cell Cycle

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The Hedgehog (Hh) pathway regulates proliferation in a variety of tissues, however its specific effects on the cell cycle are unclear. During retinal proliferation in particular, the role of Hh has been controversial, with studies variably suggesting a stimulatory or an inhibitory effect on proliferation. Our recent data provide an underlying mechanism, which reconciles these different views. We showed that Hh signaling in the retina accelerates the G 1 and G 2 phases of the cell cycle and then pushes these rapidly dividing cells out of the cell cycle prematurely. From this and other evidence, we propose that Hh converts quiescent retinal stem cells into fast-cycling transient amplifying progenitors that are closer to cell cycle exit and differentiation. This is, we suggest, likely to be a general role of Hh in the nervous system and other tissues. This function of Hh in cell cycle kinetics and cell cycle exit may have implications for tumorigenesis and brain evolution.

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A critical role for sonic hedgehog signaling in the early expansion of the developing brain

Cited by 111 publications

References 45 publications

Gli3 coordinates three-dimensional patterning and growth of the tectum and cerebellum by integrating Shh and Fgf8 signaling

Gli3 coordinates three-dimensional patterning and growth of the tectum and cerebellum by integrating Shh and Fgf8 signaling

Sonic hedgehog regulates proliferation of the retinal ciliary marginal zone in posthatch chicks

A General Role of Hedgehog in the Regulation of Proliferation

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