Midbrain-Hindbrain Boundary Morphogenesis: At the Intersection of Wnt and Fgf Signaling

Abstract

A constriction in the neural tube at the junction of the midbrain and hindbrain is a conserved feature of vertebrate embryos. The constriction is a defining feature of the midbrain-hindbrain boundary (MHB), a signaling center that patterns the adjacent midbrain and rostral hindbrain and forms at the junction of two gene expression domains in the early neural plate: an anterior otx2/wnt1 positive domain and a posterior gbx/fgf8 positive domain. otx2 and gbx genes encode mutually repressive transcription factors that create a lineage restriction boundary at their expression interface. Wnt and Fgf genes form a mutually dependent feedback system that maintains their expression domains on the otx2 or gbx side of the boundary, respectively. Constriction morphogenesis occurs after these conserved gene expression domains are established and while their mutual interactions maintain their expression pattern; consequently, mutant studies in zebrafish have led to the suggestion that constriction morphogenesis should be considered a unique phase of MHB development. We analyzed MHB morphogenesis in fgf8 loss of function zebrafish embryos using a reporter driven by the conserved wnt1 enhancer to visualize anterior boundary cells. We found that fgf8 loss of function results in a re-activation of wnt1 reporter expression posterior to the boundary simultaneous with an inactivation of the wnt1 reporter in the anterior boundary cells, and that these events correlate with relaxation of the boundary constriction. In consideration of other results that correlate the boundary constriction with Wnt and Fgf expression, we propose that the maintenance of an active Wnt-Fgf feedback loop is a key factor in driving the morphogenesis of the MHB constriction.

Spatial Fold Change of FGF Signaling Encodes Positional Information for Segmental Determination in Zebrafish

“…A fold-change detection mechanism provides robustness in signal decoding (output), allowing for variability (noise) in the encoded signal to be filtered out ( Goentoro and Kirschner, 2009 ). FGF and Wnt signaling gradients overlap in many tissues, such as lung epithelium, limb bud, prechordal plate, hindgut, and lateral line primordium ( Gibbs et al, 2017 ; Gros et al, 2010 ; Dalle Nogare and Chitnis, 2017 ; ten Berge et al, 2008 ; Volckaert and De Langhe, 2015 ). We anticipate that our explant system will be amenable to investigation into the signal decoding mechanisms and our quantitative approach applicable to other tissue patterning systems.…”

Basal constriction during midbrain-hindbrain boundary morphogenesis is mediated by Wnt5b and focal adhesion kinase

“…Since basal constriction at the zebrafish MHBC occurs within a small group of cells, one hypothesis is that a localized signaling process is involved. Wnt-PCP signaling is one candidate regulatory pathway, since this is crucial for many morphogenetic events, including gastrulation, convergent extension, cell migration, and cell adhesion ( Ciani and Salinas, 2005 ) and has been studied during the development of the midbrain–hindbrain boundary ( Buckles et al, 2004 ; Gibbs et al, 2017 ). Wnt5b is a PCP ligand and regulator of cell shape and movement.…”

The extracellular matrix–myosin pathway in mechanotransduction: from molecule to tissue

“…Cellular context is key to understanding mechanotransduction in vivo, as different cell types express different proteins that respond to force. In our opinion, two structures stand out as great models to study and understand vertebrate mechanotransduction in vivo: one is the formation of the highly conserved midbrain-hindbrain boundary (MHB) [15][16][17] and the other is the invagination of the optic cup [18,19] (Figure 2). Each structure originates from the neuroepithelium and depends on specific and unique aspects of the ECM-myosin mechanotransduction pathway.…”