Glial differentiation and the Gcm pathway

Soustelle, Laurent; Giangrande, Angela

doi:10.1017/s1740925x07000464

Cited by 25 publications

(26 citation statements)

References 62 publications

(124 reference statements)

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“…Drosophila glia arise during embryogenesis through the activity of the master regulatory gene glial cells missing (Jones, 2005;Soustelle and Giangrande, 2007). Once specified, two glial cell types can be recognized at the lateral boundary of the nervous system (Awasaki et al, 2008;Edwards and Meinertzhagen, 2010;Hartenstein, 2011;Pereanu et al, 2005;Stork et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

The regulation of glial-specific splicing ofNeurexin IVrequires HOW and Cdk12 activity

2012

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SUMMARYThe differentiation of the blood-brain barrier (BBB) is an essential process in the development of a complex nervous system and depends on alternative splicing. In the fly BBB, glial cells establish intensive septate junctions that require the cell-adhesion molecule Neurexin IV. Alternative splicing generates two different Neurexin IV isoforms: Neurexin IV exon3 , which is found in cells that form septate junctions, and Neurexin IV exon4 , which is found in neurons that form no septate junctions. Here, we show that the formation of the BBB depends on the RNA-binding protein HOW (Held out wings), which triggers glial specific splicing of Neurexin IV exon3 . Using a set of splice reporters, we show that one HOW-binding site is needed to include one of the two mutually exclusive exons 3 and 4, whereas binding at the three further motifs is needed to exclude exon 4. The differential splicing is controlled by nuclear access of HOW and can be induced in neurons following expression of nuclear HOW. Using a novel in vivo two-color splicing detector, we then screened for genes required for full HOW activity. This approach identified Cyclin-dependent kinase 12 (Cdk12) and the splicesosomal component Prp40 as major determinants in regulating HOWdependent splicing of Neurexin IV. Thus, in addition to the control of nuclear localization of HOW, the phosphorylation of the Cterminal domain of the RNA polymerase II by Cdk12 provides an elegant mechanism in regulating timed splicing of newly synthesized mRNA molecules.

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Section: Introductionmentioning

confidence: 99%

The regulation of glial-specific splicing ofNeurexin IVrequires HOW and Cdk12 activity

2012

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“…The simple Drosophila CNS makes it possible to tackle this issue in identified lineages. Moreover, a single transcription factor drives glial differentiation in Drosophila embryos: Glial cells missing (Gcm) [also called Glial cell deficient (Glide); referred to as Gcm hereafter] (for a review, see Soustelle and Giangrande, 2007). Gcm is transiently expressed in the lineages that produce glia and acts in the choice between glial and neuronal fates: its loss induces almost complete lack of glia, whereas its overexpression efficiently induces ectopic expression of the reverse polarity (repo) pan-glial gene (Bernardoni et al, 1998;Hosoya et al, 1995;Jones et al, 1995;Vincent et al, 1996) and other glial transcripts (Altenhein et al, 2006;Egger et al, 2002;Freeman et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Gcm/Glide-dependent conversion into glia depends on neural stem cell age, but not on division, triggering a chromatin signature that is conserved in vertebrate glia

et al. 2011

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SUMMARYNeurons and glia differentiate from multipotent precursors called neural stem cells (NSCs), upon the activation of specific transcription factors. In vitro, it has been shown that NSCs display very plastic features; however, one of the major challenges is to understand the bases of lineage restriction and NSC plasticity in vivo, at the cellular level. We show here that overexpression of the Gcm transcription factor, which controls the glial versus neuronal fate choice, fully and efficiently converts Drosophila NSCs towards the glial fate via an intermediate state. Gcm acts in a dose-dependent and autonomous manner by concomitantly repressing the endogenous program and inducing the glial program in the NSC. Most NSCs divide several times to build the embryonic nervous system and eventually enter quiescence: strikingly, the gliogenic potential of Gcm decreases with time and quiescent NSCs are resistant to fate conversion. Together with the fact that Gcm is able to convert mutant NSCs that cannot divide, this indicates that plasticity depends on temporal cues rather than on the mitotic potential. Finally, NSC plasticity involves specific chromatin modifications. The endogenous glial cells, as well as those induced by Gcm overexpression display low levels of histone 3 lysine 9 acetylation (H3K9ac) and Drosophila CREB-binding protein (dCBP) Histone Acetyl-Transferase (HAT). Moreover, we show that dCBP targets the H3K9 residue and that high levels of dCBP HAT disrupt gliogenesis. Thus, glial differentiation needs low levels of histone acetylation, a feature shared by vertebrate glia, calling for an epigenetic pathway conserved in evolution. KEY WORDS: Neural stem cells, Glia, Drosophila, dCBP, Gcm/Glide, Histone acetylationGcm/Glide-dependent conversion into glia depends on neural stem cell age, but not on division, triggering a chromatin signature that is conserved in vertebrate glia Hakima Flici*, Berra Erkosar*, Orban Komonyi, Omer Faruk Karatas, Pietro Laneve and Angela Giangrande † DEVELOPMENT MATERIALS AND METHODS FliesFlies were raised at 25°C unless otherwise specified. w 1118 was the wild type. Transgenic lines were: UAS-gcm (one dose: F18A: 1XGcm; two doses: M24A: 2XGcm) (Bernardoni et al., 1998); lbe(K)-Gal4, UAS-GFP (Baumgardt et al., 2009); mzVum-Gal4 (Landgraf et al., 2003); apterousGal4, UAS-mRFP (Baumgardt et al., 2007); gcm 34 / CyO,twi-LacZ (Vincent et al., 1996); UAS-dCBP and UAS-dCBP-FLAD (Kumar et al., 2004); repoGal4/TM3 (Sepp et al., 2001); repo 3692 /TM3ubx-lacZ (Halter et al., 1995); repo-Gal4 (Lee and Jones, 2005); and UAS-mCD8GFP, elavGal4, 4 /TM3 (Bloomington Drosophila Stock Center). Immunohistochemistry and in situ hybridizationImmunolabeling and in situ hybridization on embryos were as described previously (Bernardoni et al., 1998). Primary antibodies were: mouse(m)--Repo (1:50), m--Engrailed (1:500) and rat(rt)--Elav (1:200) from DSHB; chicken--GFP (1:1000), rabbit(rb)--RFP (1:500), rb--Caspase3 (1:500), m--H3K9ac (1:500), rb--H3K4me3 (1:500) from Abcam; rb--GFP (1...

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“…During nervous system development of Drosophila embryos, gcm acts as a glial determinant, being necessary and sufficient to induce the glial fate (Akiyama-Oda et al, 1998;Bernardoni et al, 1998;Hosoya et al, 1995;Jones et al, 1995;Vincent et al, 1996), for review (Soustelle and Giangrande, 2007a). Interestingly, gcm also acts as a cell fate determinant in hematopoietic lineages, where it controls the plasmatocyte/crystal cell fate choice (Alfonso and Jones, 2002;Bataille et al, 2005;Bernardoni et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…Lack of gcm leads to loss of most lateral glia, which transform into neurons, while ectopic gcm pan-neural expression leads to differentiation of supernumerary glia at the expense of neurons (Akiyama-Oda et al, 1998;Bernardoni et al, 1998;Hosoya et al, 1995;Jones et al, 1995;Vincent et al, 1996), for review (Soustelle and Giangrande, 2007a). While gcm2, the homolog of gcm, is also expressed in embryonic glial precursors, its mutation does not induce detectable glial defects, likely due to its very low levels of expression (Alfonso and Jones, 2002;Kammerer and Giangrande, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…gcm is expressed and required in embryonic hemocytes (Alfonso and Jones, 2002;Bataille et al, 2005;Bernardoni et al, 1997) and tendon cells (Soustelle et al, 2004); it is also necessary in specific neuronal and glial lineages of the post-embryonic nervous system (Chotard et al, 2005;Soustelle and Giangrande, 2007b;Soustelle et al, 2007;Yoshida et al, 2005). Importantly, gcm-dependent differentiation of these cell types relies on the activation of mutually exclusive molecular pathways (for review (Soustelle and Giangrande, 2007a).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A novel role of the glial fate determinant glial cells missing in hematopoiesis

Jacques¹,

Soustelle²,

Nagy³

et al. 2009

Int. J. Dev. Biol.

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Glial cell deficient/Glial cells missing (Glide/Gcm) transcription factor is expressed in all glial precursors of the Drosophila embryo. Gcm is necessary and sufficient to induce glial differentiation but also plays a role in other cell types, by interacting with specific factors. To find potential partners of Gcm which trigger these other pathways, we performed a yeast two-hybrid screen and identified dpias, a gene involved in post-embryonic hematopoiesis. dpias larvae show melanotic tumors due to excess of lamellocytes, a hemocyte lineage that is involved in non-self recognition. We here show that blocking Gcm activity also triggers melanotic tumors and that gcm interacts genetically with dpias. Moreover, the members of the Janus Kinase (JAK)/ Signal Transducer and Activator of Transcription (STAT) pathway, which are known for their role in the vertebrate and invertebrate immune system and are required for dpias-dependent tumor formation, act downstream of Gcm. Altogether, this study identifies an unpredicted role of Gcm, dictated by its cofactor dpias, allowing Gcm to act in a specific pathway. Together with the recent finding that glia act as scavengers during development and in pathological conditions, our data open new perspectives onto the cellular and molecular pathways involved in non-self recognition within and outside the nervous system.

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Glial differentiation and the Gcm pathway

Cited by 25 publications

References 62 publications

The regulation of glial-specific splicing ofNeurexin IVrequires HOW and Cdk12 activity

The regulation of glial-specific splicing ofNeurexin IVrequires HOW and Cdk12 activity

Gcm/Glide-dependent conversion into glia depends on neural stem cell age, but not on division, triggering a chromatin signature that is conserved in vertebrate glia

A novel role of the glial fate determinant glial cells missing in hematopoiesis

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