Engrailed and Fgf8 act synergistically to maintain the boundary between diencephalon and mesencephalon

Scholpp, Steffen; Lohs, Claudia; Brand, Michael

doi:10.1242/dev.00683

Cited by 68 publications

(64 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These data show that, when Irx1b function is perturbed, the ZLI expands into the thalamic area. In addition, the observation of a normal pretectum and unaltered formation of the PC in irx1b morphant embryos, implies normal development of the diencephalic-mesencephalic boundary, in contrast to OtxH embryos (Scholpp et al, 2003;Foucher et al, 2006). We conclude that, in embryos lacking Irx1b function, the ZLI is normally initiated at the prethalamic-thalamic junction but subsequently expands posteriorly.…”

Section: Research Articlementioning

confidence: 63%

See 1 more Smart Citation

Otx1l, Otx2 and Irx1b establish and position the ZLI in the diencephalon

et al. 2007

Self Cite

View full text Add to dashboard Cite

The thalamic complex is the major sensory relay station in the vertebrate brain and comprises three developmental subregions: the prethalamus, the thalamus and an intervening boundary region -the zona limitans intrathalamica (ZLI). Shh signalling from the ZLI confers regional identity of the flanking subregions of the ZLI, making it an important local signalling centre for regional differentiation of the diencephalon. However, our understanding of the mechanisms responsible for positioning the ZLI along the neural axis is poor. Here we show that, before ZLI formation, both Otx1l and Otx2 (collectively referred to as Otx1l/2) are expressed in spatially restricted domains. Formation of both the ZLI and the Irx1b-positive thalamus require Otx1l/2; embryos impaired in Otx1l/2 function fail to form these areas, and, instead, the adjacent pretectum and, to a lesser extent, the prethalamus expand into the mis-specified area. Conditional expression of Otx2 in these morphant embryos cell-autonomously rescues the formation of the ZLI at its correct location. Furthermore, absence of thalamic Irx1b expression, in the presence of normal Otx1l/2 function, leads to a substantial caudal broadening of the ZLI by transformation of thalamic precursors. We therefore propose that the ZLI is induced within the competence area established by Otx1l/2, and is posteriorly restricted by Irx1b.

show abstract

Section: Research Articlementioning

confidence: 63%

“…Whole-mount mRNA in situ hybridisations (ISHs) were performed as previously described (Scholpp et al, 2003). Digoxygenin-and fluoresceinlabelled probes were prepared from linearised templates using an RNA labelling kit (Roche).…”

Section: Whole-mount In Situ Hybridisationmentioning

confidence: 99%

Otx1l, Otx2 and Irx1b establish and position the ZLI in the diencephalon

et al. 2007

Self Cite

View full text Add to dashboard Cite

show abstract

“…We tested whether Wnt and FGF signalling regulate MTN development using zebrafish mutants, transgenics and small-molecule regulators. Abrogation of FGF signalling in fgf8a hypomorphic mutants or after treatment with the FGF receptor inhibitor SU5402 from 14 hpf, when midbrain specification has occurred (Scholpp et al, 2003), resulted in an increased number of MTN neurons ( Fig. 2A,B,K); by contrast, upregulation of FGF activity by overexpression of a constitutively active Fgf receptor 1 (CA-fgfr1) at 16.5 hpf resulted in fewer MTN neurons than in control animals ( Fig.…”

Section: Mtn Formation Is Regulated By Wnt and Fgf Signallingmentioning

confidence: 99%

A bi-modal function of Wnt signalling directs an FGF activity gradient to spatially regulate neuronal differentiation in the midbrain

et al. 2014

View full text Add to dashboard Cite

FGFs and Wnts are important morphogens during midbrain development, but their importance and potential interactions during neurogenesis are poorly understood. We have employed a combination of genetic and pharmacological manipulations in zebrafish to show that during neurogenesis FGF activity occurs as a gradient along the anterior-posterior axis of the dorsal midbrain and directs spatially dynamic expression of the Hairy gene her5. As FGF activity diminishes during development, Her5 is lost and differentiation of neuronal progenitors occurs in an anterior-posterior manner. We generated mathematical models to explain how Wnt and FGFs direct the spatial differentiation of neurons in the midbrain through Wnt regulation of FGF signalling. These models suggested that a negative-feedback loop controlled by Wnt is crucial for regulating FGF activity. We tested Sprouty genes as mediators of this regulatory loop using conditional mouse knockouts and pharmacological manipulations in zebrafish. These reveal that Sprouty genes direct the positioning of early midbrain neurons and are Wnt responsive in the midbrain. We propose a model in which Wnt regulates FGF activity at the isthmus by driving both FGF and Sprouty gene expression. This controls a dynamic, posteriorly retracting expression of her5 that directs neuronal differentiation in a precise spatiotemporal manner in the midbrain.

show abstract

“…Engrailed 1 and 2 (En1/2) are important for DA neuron generation and survival (Alberi et al, 2004;Alvarez-Fischer et al, 2011;Alves dos Santos and Smidt, 2011;Ellisor et al, 2012;Nordström et al, 2015;Rekaik et al, 2015;Simon et al, 2001;Veenvliet et al, 2013). Moreover, engrailed proteins are involved in various boundary formation systems such as the diencephalic-dorsal midbrain boundary (Matsunaga et al, 2000;Scholpp et al, 2003) and a D-V boundary in the limb apical ectodermal ridge (Kimmel et al, 2000). In contrast, developing brain homeobox 1 (Dbx1) expression is excluded from the ventral midbrain, but is expressed in the caudal ventral diencephalon at this stage (Causeret et al, 2011;Shoji et al, 1996;Sokolowski et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

A novel floor plate boundary defined by adjacentEn1andDbx1microdomains distinguishes midbrain dopamine and hypothalamic neurons

Nouri

Awatramani

2017

Development

View full text Add to dashboard Cite

The mesodiencephalic floor plate (mdFP) is the source of diverse neuron types. Yet, how this structure is compartmentalized has not been clearly elucidated. Here, we identify a novel boundary subdividing the mdFP into two microdomains, defined by engrailed 1 (En1) and developing brain homeobox 1 (Dbx1). Utilizing simultaneous dual and intersectional fate mapping, we demonstrate that this boundary is precisely formed with minimal overlap between En1 and Dbx1 microdomains, unlike many other boundaries. We show that the En1 microdomain gives rise to dopaminergic (DA) neurons, whereas the Dbx1 microdomain gives rise to subthalamic (STN), premammillary (PM) and posterior hypothalamic (PH) populations. To determine whether En1 is sufficient to induce DA neuron production beyond its normal limit, we generated a mouse strain that expresses En1 in the Dbx1 microdomain. In mutants, we observed ectopic production of DA neurons derived from the Dbx1 microdomain, at the expense of STN and PM populations. Our findings provide new insights into subdivisions in the mdFP, and will impact current strategies for the conversion of stem cells into DA neurons.

show abstract

Engrailed and Fgf8 act synergistically to maintain the boundary between diencephalon and mesencephalon

Abstract: SummaryEngrailed and Fgf8 act synergistically to maintain the boundary between diencephalon and mesencephalon

Cited by 68 publications

References 69 publications

Otx1l, Otx2 and Irx1b establish and position the ZLI in the diencephalon

Otx1l, Otx2 and Irx1b establish and position the ZLI in the diencephalon

A bi-modal function of Wnt signalling directs an FGF activity gradient to spatially regulate neuronal differentiation in the midbrain

A novel floor plate boundary defined by adjacentEn1andDbx1microdomains distinguishes midbrain dopamine and hypothalamic neurons

Contact Info

Product

Resources

About