Les lincRNAs dans le développement des vertébrés

Publications de l’équipe

Année de publication : 2005

Jochen A Stadler, Alena Shkumatava, William H J Norton, Marlene J Rau, Robert Geisler, Sabine Fischer, Carl J Neumann (2005 May 17)

Histone deacetylase 1 is required for cell cycle exit and differentiation in the zebrafish retina.

Developmental dynamics : an official publication of the American Association of Anatomists : 883-9 En savoir plus

Histone acetylation is an important epigenetic mechanism for the control of eukaryotic transcription. The histone deacetylase 1 (HDAC1) gene has been implicated in controlling the transcription of core cell cycle regulators, but the in vivo role of HDACs in cell cycle regulation is still poorly understood. Loss of HDAC1 activity causes underproliferation in several contexts during vertebrate development. In contrast, we show here that HDAC1 has the opposite effect in the zebrafish visual system, where loss of HDAC1 activity leads to failure of cells to exit the cell cycle in the retina and in the optic stalk. The effect of HDAC1 on cell cycle exit is cell-autonomous, and loss of HDAC1 in the retina leads to up-regulation of cyclin D and E transcripts. These results demonstrate that the in vivo role of HDAC1 in regulating cell cycle progression is region-specific, as HDAC1 promotes cell cycle exit in the retina but stimulates proliferation in other cellular contexts.

Alena Shkumatava, Carl J Neumann (2005 May 14)

Shh directs cell-cycle exit by activating p57Kip2 in the zebrafish retina.

EMBO reports : 563-9 En savoir plus

The Hedgehog (Hh) family of signalling proteins control both differentiation and proliferation during animal development. Previous studies have shown that Hh signalling has a stimulatory effect on the cell cycle in several organs by controlling core cell-cycle components. Here, we show that Sonic hedgehog (Shh) signalling has the opposite effect in the zebrafish retina, where it leads to cell-cycle exit, and that this is mediated by transcriptional activation of the cyclin kinase inhibitor p57Kip2. The loss of p57Kip2 activity strongly resembles the Shh mutant eye phenotype, and overexpression of p57Kip2 rescues cell-cycle exit in Shh mutants, indicating that p57Kip2 is both necessary and sufficient to mediate Shh-induced cell-cycle exit in the retina. These findings raise the possibility that stimulation of cell-cycle exit through regulation of core cell-cycle components may be part of a general mechanism required for Hh-directed differentiation.

Jochen A Stadler, Alena Shkumatava, Carl J Neumann (2005 Apr 28)

The role of hedgehog signaling in the development of the zebrafish visual system.

Developmental neuroscience : 346-51 En savoir plus

The vertebrate visual system is a region of the nervous system that is characterized by relative simplicity, and its development has hence been studied intensively, to serve as a paradigm for the rest of the central nervous system. The zebrafish model organism offers an impressive array of tools to dissect this process experimentally, and in recent years has helped to significantly deepen our understanding of the development of the visual system. A number of these studies have focused on the role of the Hedgehog family of secreted signaling molecules in eye development, and this is the main topic of this review. Hedgehog signaling plays an important role in all major steps of visual system development, starting with the regionalization of the eye primordium into proximal and distal territories, continuing with the control of cellular differentiation in the retina, and ending with the guidance of axonal projections from the retina to the optic centers of the brain.


Année de publication : 2004

Alena Shkumatava, Sabine Fischer, Ferenc Müller, Uwe Strahle, Carl J Neumann (2004 Jul 16)

Sonic hedgehog, secreted by amacrine cells, acts as a short-range signal to direct differentiation and lamination in the zebrafish retina.

Development (Cambridge, England) : 3849-58 En savoir plus

Neurogenesis in the zebrafish retina occurs in several waves of differentiation. The first neurogenic wave generates ganglion cells and depends on hedgehog (hh) signaling activity. Using transgenic zebrafish embryos that express GFP under the control of the sonic hedgehog (shh) promoter, we imaged the differentiation wave in the retina and show that, in addition to the wave in the ganglion cell layer, shh expression also spreads in the inner nuclear layer. This second wave generates amacrine cells expressing shh, and although it overlaps temporally with the first wave, it does not depend on it, as it occurs in the absence of ganglion cells. We also show that differentiation of cell types found in the inner and outer nuclear layers, as well as lamination of the retina, depends on shh. By performing mosaic analysis, we demonstrate that Shh directs these events as a short-range signal within the neural retina.


Année de publication : 2003

Bernhard Schmierer, Michael K Schuster, Alena Shkumatava, Karl Kuchler (2003 Apr 1)

Activin a signaling induces Smad2, but not Smad3, requiring protein kinase a activity in granulosa cells from the avian ovary.

The Journal of biological chemistry : 21197-203 En savoir plus

Activin A signaling is an important regulator of ovarian granulosa cell function. The cytosolic signal transducer Smad2 is most highly expressed in chicken granulosa cells (cGC) of preovulatory follicles. Moreover, Smad2 shows predominant nuclear localization in freshly isolated cGC, indicating active Smad signaling in vivo. Primary cGC cultured in vitro require activin A to sustain high Smad2 levels, which otherwise drop dramatically in the absence of activin A. This activin A-dependent Smad2 expression is abrogated by protein kinase A (PKA) inhibitors, suggesting a role for PKA in activin signaling. In the absence of activin A, strong PKA activators such as follicle-stimulating hormone (FSH) and 8-bromo-cyclic AMP fail to elicit Smad2 induction. However, FSH and 8-bromo-cyclic AMP boost activin A-dependent Smad2 up-regulation, giving rise to Smad2 levels similar to expression in vivo levels. Interestingly, the effect is specific for Smad2, since expression of the structurally and functionally closely related Smad3 remains entirely unaffected. Hence, activin A induces Smad2, but not Smad3, to high levels requiring PKA activation. Since Smad2 and Smad3 target distinct yet overlapping sets of TGF-beta/activin-responsive genes, the selective Smad2 induction by FSH/activin A could allow FSH to efficiently modulate the transcriptional readout of activin A signaling in avian granulosa cells.

Bernhard Schmierer, Michael K Schuster, Alena Shkumatava, Karl Kuchler (2003 Jan 21)

Activin and follicle-stimulating hormone signaling are required for long-term culture of functionally differentiated primary granulosa cells from the chicken ovary.

Biology of reproduction : 620-7 En savoir plus

Follicle-stimulating hormone, activin A, and transforming growth factor (TGF) alpha are important regulators of chicken granulosa cell (cGC) function. Hence, we aimed to test whether these growth factors are useful for establishing a suitable in vitro cell culture model system of primary cGC. Although cGC are easily isolated from distinct follicular stages, a long-term cGC culture system for in vitro studies has been unavailable. Here, we report a novel, long-term cell culture system that allows for cGC proliferation in vitro while maintaining the epithelial phenotype that granulosa cells exhibit in vivo. The cGC rapidly lose their epithelial morphology and acquire a mesenchymal or fibroblastoid phenotype when cultured in the absence of activin A. This process is strongly enhanced by TGFalpha, a well-known granulosa cell mitogen. However, FSH stimulates cGC proliferation without enhancing morphological changes and dedifferentiation. Interestingly, a combination of both activin A and FSH stimulates cGC proliferation and supports maintenance of differentiated epithelial morphology. Furthermore, activin A and FSH synergistically induce granulosa cell-specific differentiation markers such as inhibin alpha and chicken zona pellucida protein C, suggesting that cultured cGC resemble functionally differentiated granulosa cells. Our data demonstrate that activin signaling is necessary to sustain a morphologically differentiated phenotype of cGC in vitro. The results also suggest a pivotal importance of activin signaling for granulosa cell function in vivo.