<i>Gbx2</i> and <i>Fgf8</i> are sequentially required for formation of the midbrain-hindbrain compartment boundary

Sunmonu, N. Abimbola; Li, Kairong; Guo, Qiu

doi:10.1242/dev.055665

Cited by 49 publications

(56 citation statements)

References 41 publications

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“…However, in the absence of both of these genes, MHB organiser genes remain expressed, although their expression is not restricted to the boundary, indicating that these genes are important for the spatial refinement, rather than the induction, of genes associated with the organiser (Li and Joyner, 2001;Martinez-Barbera et al, 2001). Recent work has shown that differential expression of Otx2 and Gbx2 contributes to the segregation of midbrain and hindbrain cells, yet the mechanisms by which these two genes determine the position of the boundary are unclear, particularly as they function as transcriptional repressors (Glavic et al, 2002;Sunmonu et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Once induced, MHB organiser genes become interdependent through complex crossregulatory networks that stabilise and maintain the organiser (Rhinn and Brand, 2001;Wurst and Bally-Cuif, 2001). In particular, Fgf8 has been shown to be important in maintaining lineage restriction at the boundary (Sunmonu et al, 2011).…”

Section: Notch Specifies Boundary Cell Fatementioning

confidence: 99%

“…Experimentally shifting their expression border using transgenic mice to drive Gbx2 more anteriorly or Otx2 more posteriorly results in a corresponding shift in the position of the MHB (Broccoli et al, 1999;Katahira et al, 2000;Millet et al, 1999). Furthermore, differential expression of Otx2 and Gbx2 in midbrain and anterior hindbrain cells leads to the initial segregation of these cell types (Sunmonu et al, 2011). Therefore, Otx2 and Gbx2 play a key role in MHB formation by creating two adjacent territories of different cell states, at the junction of which a boundary/organiser cell is induced.…”

Section: Introductionmentioning

confidence: 99%

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Notch signalling stabilises boundary formation at the midbrain-hindbrain organiser

et al. 2011

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The midbrain-hindbrain interface gives rise to a boundary of particular importance in CNS development as it forms a local signalling centre, the proper functioning of which is essential for the formation of tectum and cerebellum. Positioning of the mid-hindbrain boundary (MHB) within the neuroepithelium is dependent on the interface of Otx2 and Gbx2 expression domains, yet in the absence of either or both of these genes, organiser genes are still expressed, suggesting that other, as yet unknown mechanisms are also involved in MHB establishment. Here, we present evidence for a role for Notch signalling in stabilising cell lineage restriction and regulating organiser gene expression at the MHB. Experimental interference with Notch signalling in the chick embryo disrupts MHB formation, including downregulation of the organiser signal Fgf8. Ectopic activation of Notch signalling in cells of the anterior hindbrain results in an exclusion of those cells from rhombomeres 1 and 2, and in a simultaneous clustering along the anterior and posterior boundaries of this area, suggesting that Notch signalling influences cell sorting. These cells ectopically express the boundary marker Fgf3. In agreement with a role for Notch signalling in cell sorting, anterior hindbrain cells with activated Notch signalling segregate from normal cells in an aggregation assay. Finally, misexpression of the Notch modulator Lfng or the Notch ligand Ser1 across the MHB leads to a shift in boundary position and loss of restriction of Fgf8 to the MHB. We propose that differential Notch signalling stabilises the MHB through regulating cell sorting and specifying boundary cell fate.

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Section: Discussionmentioning

confidence: 99%

Section: Notch Specifies Boundary Cell Fatementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Notch signalling stabilises boundary formation at the midbrain-hindbrain organiser

et al. 2011

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“…In addition to the co-repressive actions of Otx2 and Gbx2 at the boundary, Fgf8, Gbx2 and Notch signalling (Sunmonu et al, 2011;Tossell et al, 2011) promote cell sorting and, hence, lineage restriction at the boundary. The signalling molecule Fgf8 also has a key role in establishing and maintaining the cerebellar boundary.…”

Section: The Cerebellar Anlage Sits Between Hox and Otx Domainsmentioning

confidence: 99%

Development of the cerebellum: simple steps to make a ‘little brain’

Green²,

2014

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The cerebellum is a pre-eminent model for the study of neurogenesis and circuit assembly. Increasing interest in the cerebellum as a participant in higher cognitive processes and as a locus for a range of disorders and diseases make this simple yet elusive structure an important model in a number of fields. In recent years, our understanding of some of the more familiar aspects of cerebellar growth, such as its territorial allocation and the origin of its various cell types, has undergone major recalibration. Furthermore, owing to its stereotyped circuitry across a range of species, insights from a variety of species have contributed to an increasingly rich picture of how this system develops. Here, we review these recent advances and explore three distinct aspects of cerebellar development -allocation of the cerebellar anlage, the significance of transit amplification and the generation of neuronal diversity -each defined by distinct regulatory mechanisms and each with special significance for health and disease.

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“…As conditional deletion using creER creates genetic mosaicism (supplementary material Fig. S2) (Chen et al, 2009;Sunmonu et al, 2011), the guidance defects in Gbx2-CKO mutants thus reflect a cell-autonomous function of Gbx2. These in vivo studies, together with the explant assays ( Fig.…”

Section: Pathfinding Defects Of Tcas and Abnormal Robo Expression In mentioning

confidence: 99%

Gbx2 regulates thalamocortical axon guidance by modifying the LIM and Robo codes

Chatterjee

Chen

et al. 2012

Development

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SUMMARYCombinatorial expression of transcription factors forms transcriptional codes to confer neuronal identities and connectivity. However, how these intrinsic factors orchestrate the spatiotemporal expression of guidance molecules to dictate the responsiveness of axons to guidance cues is less understood. Thalamocortical axons (TCAs) represent the major input to the neocortex and modulate cognitive functions, consciousness and alertness. TCAs travel a long distance and make multiple target choices en route to the cortex. The homeodomain transcription factor Gbx2 is essential for TCA development, as loss of Gbx2 abolishes TCAs in mice. Using a novel TCAspecific reporter, we have discovered that thalamic axons are mostly misrouted to the ventral midbrain and dorsal midline of the diencephalon in Gbx2-deficient mice. Furthermore, conditionally deleting Gbx2 at different embryonic stages has revealed a sustained role of Gbx2 in regulating TCA navigation and targeting. Using explant culture and mosaic analyses, we demonstrate that Gbx2 controls the intrinsic responsiveness of TCAs to guidance cues. The guidance defects of Gbx2-deficient TCAs are associated with abnormal expression of guidance receptors Robo1 and Robo2. Finally, we demonstrate that Gbx2 controls Robo expression by regulating LIM-domain transcription factors through three different mechanisms: Gbx2 and Lhx2 compete for binding to the Lmo3 promoter and exert opposing effects on its transcription; repressing Lmo3 by Gbx2 is essential for Lhx2 activity to induce Robo2; and Gbx2 represses Lhx9 transcription, which in turn induces Robo1. Our findings illustrate the transcriptional control of differential expression of Robo1 and Robo2, which may play an important role in establishing the topography of TCAs.

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Gbx2 and Fgf8 are sequentially required for formation of the midbrain-hindbrain compartment boundary

Cited by 49 publications

References 41 publications

Notch signalling stabilises boundary formation at the midbrain-hindbrain organiser

Notch signalling stabilises boundary formation at the midbrain-hindbrain organiser

Development of the cerebellum: simple steps to make a ‘little brain’

Gbx2 regulates thalamocortical axon guidance by modifying the LIM and Robo codes

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