Dynamic Coupling of Pattern Formation and Morphogenesis in the Developing Vertebrate Retina

Picker, Alexander; Cavodeassi, Florencia; Machate, Anja; Bernauer, Sabine; Hans, Stefan; Abe, Gembu; Kawakami, Koichi; Wilson, Stephen W.; Brand, Michael

doi:10.1371/journal.pbio.1000214

Cited by 109 publications

(154 citation statements)

References 71 publications

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“…This result is particularly noteworthy, because unlike previous studies of FGF signaling in Xenopus and zebrafish (Take-uchi et al, 2003;Lupo et al, 2005;Picker and Brand, 2005;Picker et al, 2009), our Fgfr1/2 mutants did not display any axial polarity defects, suggesting that the observed ocular coloboma and optic nerve dysgenesis was not secondary to abnormal patterning of early optic cup. As indicated by the misexpression of the ocular astrocyte progenitor cell (APC) marker Pax2 and the RPE gene Mitf, loss of Fgfr1/2 signaling transformed the presumptive optic disc and optic fissure into RPE, suggesting a crucial role for FGF signaling in promoting the astrocyte progenitor cell fate versus the RPE fate.…”

Section: Discussioncontrasting

confidence: 62%

Deficient FGF signaling causes optic nerve dysgenesis and ocular coloboma

Cai

Tao

et al. 2013

Development

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SUMMARYFGF signaling plays a pivotal role in eye development. Previous studies using in vitro chick models and systemic zebrafish mutants have suggested that FGF signaling is required for the patterning and specification of the optic vesicle, but due to a lack of genetic models, its role in mammalian retinal development remains elusive. In this study, we show that specific deletion of Fgfr1 and Fgfr2 in the optic vesicle disrupts ERK signaling, which results in optic disc and nerve dysgenesis and, ultimately, ocular coloboma. Defective FGF signaling does not abrogate Shh or BMP signaling, nor does it affect axial patterning of the optic vesicle. Instead, FGF signaling regulates Mitf and Pax2 in coordinating the closure of the optic fissure and optic disc specification, which is necessary for the outgrowth of the optic nerve. Genetic evidence further supports that the formation of an Frs2α-Shp2 complex and its recruitment to FGF receptors are crucial for downstream ERK signaling in this process, whereas constitutively active Ras signaling can rescue ocular coloboma in the FGF signaling mutants. Our results thus reveal a previously unappreciated role of FGF-Frs2α-Shp2-Ras-ERK signaling axis in preventing ocular coloboma. These findings suggest that components of FGF signaling pathway may be novel targets in the diagnosis of and the therapeutic interventions for congenital ocular anomalies.

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Section: Discussioncontrasting

confidence: 62%

Deficient FGF signaling causes optic nerve dysgenesis and ocular coloboma

Cai

Tao

et al. 2013

Development

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“…In agreement with this, regionalization but not vesicle cohesion is defective in the double morphants. A similar delamination phenotype is seen with knockdown of Foxg1a (Picker et al, 2009), though the loss of cells appears to occur earlier in plxna2 morphants. Loss of epithelial contacts could in part explain We suggest a tissue-autonomous role for Sema6a/Plxna2, where Plxna2 neutralizes Sema6a repulsion in the ventral (V) domain, leaving the dorsal (D) vesicle as repulsive (red bars).…”

Section: Discussionmentioning

confidence: 52%

“…We evaluated the expression of several transcription factors at 12 somites. fogx1a, a transcription factor expressed in the dorsal (future nasal) eye vesicle (Picker et al, 2009), expands into ventral domains in plxna2 and sema6a morphants (Fig. 7A-C).…”

Section: Plxna2 Required For Regionalization Of the Developing Eyementioning

confidence: 99%

Sema6a and Plxna2 mediate spatially regulated repulsion within the developing eye to promote eye vesicle cohesion

et al. 2014

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Organs are generated from collections of cells that coalesce and remain together as they undergo a series of choreographed movements to give the organ its final shape. We know little about the cellular and molecular mechanisms that regulate tissue cohesion during morphogenesis. Extensive cell movements underlie eye development, starting with the eye field separating to form bilateral vesicles that go on to evaginate from the forebrain. What keeps eye cells together as they undergo morphogenesis and extensive proliferation is unknown. Here, we show that plexina2 (Plxna2), a member of a receptor family best known for its roles in axon and cell guidance, is required alongside the repellent semaphorin 6a (Sema6a) to keep cells integrated within the zebrafish eye vesicle epithelium. sema6a is expressed throughout the eye vesicle, whereas plxna2 is restricted to the ventral vesicle. Knockdown of Plxna2 or Sema6a results in a loss of vesicle integrity, with time-lapse microscopy showing that eye progenitors either fail to enter the evaginating vesicles or delaminate from the eye epithelium. Explant experiments, and rescue of eye vesicle integrity with simultaneous knockdown of sema6a and plxna2, point to an eye-autonomous requirement for Sema6a/Plxna2. We propose a novel, tissue-autonomous mechanism of organ cohesion, with neutralization of repulsion suggested as a means to promote interactions between cells within a tissue domain.

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“…Foxg1 encodes for a winged-helix TF expressed by rostral CNS and sense organs, crucial for their morphogenesis [43][44][45][46][47][48]. It is involved in several aspects of telencephalic development, including specification of the telencephalic field [49], specification of basal ganglia, paleo-and neo-cortex [48,50,51], and cortical laminar specification [21,52].…”

Section: Introductionmentioning

confidence: 99%

Emx2 and Foxg1 Inhibit Gliogenesis and Promote Neuronogenesis

et al. 2010

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Neural stem cells (NSCs) give rise to all cell types forming the cortex: neurons, astrocytes, and oligodendrocytes. The transition from the former to the latter ones takes place via lineage-restricted progenitors in a highly regulated way. This process is mastered by large sets of genes, among which some implicated in central nervous system pattern formation. The aim of this study was to disentangle the kinetic and histogenetic roles exerted by two of these genes, Emx2 and Foxg1, in cortico-cerebral precursors. For this purpose, we set up a new integrated in vitro assay design. Embryonic cortical progenitors were transduced with lentiviral vectors driving overexpression of Emx2 and Foxg1 in NSCs and neuronal progenitors. Cells belonging to different neuronogenic and gliogenic compartments were labeled by spectrally distinguishable fluoroproteins driven by cell type-specific promoters and by cell type-specific antibodies and were scored via multiplex cytofluorometry and immunocytofluorescence. A detailed picture of Emx2 and Foxg1 activities in cortico-cerebral histogenesis resulted from this study. Unexpectedly, we found that both genes inhibit gliogenesis and promote neuronogenesis, through distinct mechanisms, and Foxg1 also dramatically stimulates neurite outgrowth. Remarkably, such activities, alone or combined, may be exploited to ameliorate the neuronal output obtainable from neural cultures, for purposes of cell-based brain repair. STEM CELLS

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Dynamic Coupling of Pattern Formation and Morphogenesis in the Developing Vertebrate Retina

Abstract: In this Research Article, Picker et al. show how cells in the retina get their spatial coordinates.

Cited by 109 publications

References 71 publications

Deficient FGF signaling causes optic nerve dysgenesis and ocular coloboma

Deficient FGF signaling causes optic nerve dysgenesis and ocular coloboma

Sema6a and Plxna2 mediate spatially regulated repulsion within the developing eye to promote eye vesicle cohesion

Emx2 and Foxg1 Inhibit Gliogenesis and Promote Neuronogenesis

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