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Expression of hindbrain boundary markers is regulated by FGF3.

ABSTRACT: Compartment boundaries act as organizing centers that segregate adjacent areas into domains of gene expression and regulation, and control their distinct fates via the secretion of signalling factors. During hindbrain development, a specialized cell-population forms boundaries between rhombomeres. These boundary cells demonstrate unique morphological properties and express multiple genes that differs them from intra-rhombomeric cells. Yet, little is known regarding the mechanisms that controls the expression or function of these boundary markers.Multiple components of the FGF signaling system, including ligands, receptors, downstream effectors as well as proteoglycans are shown to localize to boundary cells in the chick hindbrain. These patterns raise the possibility that FGF signaling plays a role in regulating boundary properties. We provide evidence to the role of FGF signaling, particularly the boundary-derived FGF3, in regulating the expression of multiple markers at hindbrain boundaries. These findings enable further characterization of the unique boundary-cell population, and expose a new function for FGFs as regulators of boundary-gene expression in the chick hindbrain.

SUBMITTER: Weisinger K

PROVIDER: S-EPMC3507201 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Expression of hindbrain boundary markers is regulated by FGF3.

Weisinger Karen K Kohl Ayelet A Kayam Galya G Monsonego-Ornan Efrat E Sela-Donenfeld Dalit D

Biology open 20111101 2

Compartment boundaries act as organizing centers that segregate adjacent areas into domains of gene expression and regulation, and control their distinct fates via the secretion of signalling factors. During hindbrain development, a specialized cell-population forms boundaries between rhombomeres. These boundary cells demonstrate unique morphological properties and express multiple genes that differs them from intra-rhombomeric cells. Yet, little is known regarding the mechanisms that controls t ...[more]

PMID: 23213398

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Project description:BackgroundThe establishment of the mid-hindbrain region in vertebrates is mediated by the isthmic organizer, an embryonic secondary organizer characterized by a well-defined pattern of locally restricted gene expression domains with sharply delimited boundaries. While the function of the isthmic organizer at the mid-hindbrain boundary has been subject to extensive experimental studies, it remains unclear how this well-defined spatial gene expression pattern, which is essential for proper isthmic organizer function, is established during vertebrate development. Because the secreted Wnt1 protein plays a prominent role in isthmic organizer function, we focused in particular on the refinement of Wnt1 gene expression in this context.ResultsWe analyzed the dynamics of the corresponding murine gene regulatory network and the related, diffusive signaling proteins using a macroscopic model for the biological two-scale signaling process. Despite the discontinuity arising from the sharp gene expression domain boundaries, we proved the existence of unique, positive solutions for the partial differential equation system. This enabled the numerically and analytically analysis of the formation and stability of the expression pattern. Notably, the calculated expression domain of Wnt1 has no sharp boundary in contrast to experimental evidence. We subsequently propose a post-transcriptional regulatory mechanism for Wnt1 miRNAs which yields the observed sharp expression domain boundaries. We established a list of candidate miRNAs and confirmed their expression pattern by radioactive in situ hybridization. The miRNA miR-709 was identified as a potential regulator of Wnt1 mRNA, which was validated by luciferase sensor assays.ConclusionIn summary, our theoretical analysis of the gene expression pattern induction at the mid-hindbrain boundary revealed the need to extend the model by an additional Wnt1 regulation. The developed macroscopic model of a two-scale process facilitate the stringent analysis of other morphogen-based patterning processes.

Project description:BackgroundStudies in mouse, Xenopus and chicken have shown that Otx2 and Gbx2 expression domains are fundamental for positioning the midbrain-hindbrain boundary (MHB) organizer. Of the two zebrafish gbx genes, gbx1 is a likely candidate to participate in this event because its early expression is similar to that reported for Gbx2 in other species. Zebrafish gbx2, on the other hand, acts relatively late at the MHB. To investigate the function of zebrafish gbx1 within the early neural plate, we used a combination of gain- and loss-of-function experiments.ResultsWe found that ectopic gbx1 expression in the anterior neural plate reduces forebrain and midbrain, represses otx2 expression and repositions the MHB to a more anterior position at the new gbx1/otx2 border. In the case of gbx1 loss-of-function, the initially robust otx2 domain shifts slightly posterior at a given stage (70% epiboly), as does MHB marker expression. We further found that ectopic juxtaposition of otx2 and gbx1 leads to ectopic activation of MHB markers fgf8, pax2.1 and eng2. This indicates that, in zebrafish, an interaction between otx2 and gbx1 determines the site of MHB development. Our work also highlights a novel requirement for gbx1 in hindbrain development. Using cell-tracing experiments, gbx1 was found to cell-autonomously transform anterior neural tissue into posterior. Previous studies have shown that gbx1 is a target of Wnt8 graded activity in the early neural plate. Consistent with this, we show that gbx1 can partially restore hindbrain patterning in cases of Wnt8 loss-of-function. We propose that in addition to its role at the MHB, gbx1 acts at the transcriptional level to mediate Wnt8 posteriorizing signals that pattern the developing hindbrain.ConclusionOur results provide evidence that zebrafish gbx1 is involved in positioning the MHB in the early neural plate by refining the otx2 expression domain. In addition to its role in MHB formation, we have shown that gbx1 is a novel mediator of Wnt8 signaling during hindbrain patterning.

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Expression of hindbrain boundary markers is regulated by FGF3.

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Expression of hindbrain boundary markers is regulated by FGF3.

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