Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature

Organogenesis and Neurogenesis Group, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan.
Nature (Impact Factor: 41.46). 04/2011; 472(7341):51-6. DOI: 10.1038/nature09941
Source: PubMed


Balanced organogenesis requires the orchestration of multiple cellular interactions to create the collective cell behaviours that progressively shape developing tissues. It is currently unclear how individual, localized parts are able to coordinate with each other to develop a whole organ shape. Here we report the dynamic, autonomous formation of the optic cup (retinal primordium) structure from a three-dimensional culture of mouse embryonic stem cell aggregates. Embryonic-stem-cell-derived retinal epithelium spontaneously formed hemispherical epithelial vesicles that became patterned along their proximal-distal axis. Whereas the proximal portion differentiated into mechanically rigid pigment epithelium, the flexible distal portion progressively folded inward to form a shape reminiscent of the embryonic optic cup, exhibited interkinetic nuclear migration and generated stratified neural retinal tissue, as seen in vivo. We demonstrate that optic-cup morphogenesis in this simple cell culture depends on an intrinsic self-organizing program involving stepwise and domain-specific regulation of local epithelial properties.

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Available from: Taiji Adachi, Sep 08, 2014
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    • "Subsequently, the apical side of the NR gradually expands more than the basal side to complete invagination. Once the NR field is specified, NE cells start neurogenesis following a temporal pattern that mimics the in vivo situation, enabling the sequential generation of various retinal cell populations organized in a layer-like structure, which resembles the early neonatal eye of rodents (Eiraku et al., 2011; Nakano et al., 2012; Osakada et al., 2009) (Fig. 4B). Another aspect of the selforganizing property of retinal development from human PSCs was demonstrated more recently (Kuwahara et al., 2015), in which a specific stem cell niche called the retinal ciliary margin (RCM) (Agathocleous and Harris, 2009),which is located at the boundary of the NR and RPE, could be generated in vitro and displayed the potential to produce retinal progenitors, which in turn generate various retinal subtypes including photoreceptors (Fig. 4C). "
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    ABSTRACT: The human brain is arguably the most complex structure among living organisms. However, the specific mechanisms leading to this complexity remain incompletely understood, primarily because of the poor experimental accessibility of the human embryonic brain. Over recent years, technologies based on pluripotent stem cells (PSCs) have been developed to generate neural cells of various types. While the translational potential of PSC technologies for disease modeling and/or cell replacement therapies is usually put forward as a rationale for their utility, they are also opening novel windows for direct observation and experimentation of the basic mechanisms of human brain development. PSC-based studies have revealed that a number of cardinal features of neural ontogenesis are remarkably conserved in human models, which can be studied in a reductionist fashion. They have also revealed species-specific features, which constitute attractive lines of investigation to elucidate the mechanisms underlying the development of the human brain, and its link with evolution.
    Development 09/2015; 142(18):3138-3150. DOI:10.1242/dev.120568 · 6.46 Impact Factor
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    • "Organogenesis of ectodermal organs, such as teeth (Fig. S1 and Text S1 in the Supporting material), hair, and the optic cup, involves a large-scale deformation process that is critical for later development (Eiraku et al., 2011; Jernvall et al., 1994; Paus et al., 1999; Toyoshima et al., 2012; Vaahtokari et al., 1996). In the early stage of tooth development, a bud of dental epithelium grows into a cap structure with an invaginated tip (Fig. 1A, white arrowhead). "
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    ABSTRACT: In the early stage of tooth germ development, the bud of the dental epithelium is invaginated by the underlying mesenchyme, resulting in the formation of a cap-like folded shape. This bud-to-cap transition plays a critical role in determining the steric design of the tooth. The epithelial-mesenchymal interaction within a tooth germ is essential for mediating the bud-to-cap transition. Here, we present a theoretical model to describe the autonomous process of the morphological transition, in which we introduce mechanical interactions among cells. Based on our observations, we assumed that peripheral cells of the dental epithelium bound tightly to each other to form an elastic sheet, and mesenchymal cells that covered the tooth germ would restrict its growth. By considering the time-dependent growth of cells, we were able to numerically show that the epithelium within the tooth germ buckled spontaneously, which is reminiscent of the cap-stage form. The difference in growth rates between the peripheral and interior parts of the dental epithelium, together with the steric size of the tooth germ, were determining factors for the number of invaginations. Our theoretical results provide a new hypothesis to explain the histological features of the tooth germ. Copyright © 2015. Published by Elsevier Ltd.
    Journal of Theoretical Biology 07/2015; 382. DOI:10.1016/j.jtbi.2015.07.006 · 2.12 Impact Factor
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    • "Studies from 3D stem cell differentiation assays have confusingly suggested that neural stem cells spontaneously generate cells of retinal identity (Eiraku et al., 2011) or cerebral cortical (dorsal telencephalic) character (Lancaster et al., 2013). In light of our model, it is possible that the presence or absence of low levels of endogenous BMP signals in these assays directs the generation of retinal versus cerebral cortical cells. "
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    ABSTRACT: The eye has served as a classical model to study cell specification and tissue induction for over a century. Nevertheless, the molecular mechanisms that regulate the induction and maintenance of eye-field cells, and the specification of neural retina cells are poorly understood. Moreover, within the developing anterior forebrain, how prospective eye and telencephalic cells are differentially specified is not well defined. In the present study, we have analyzed these issues by manipulating signaling pathways in intact chick embryo and explant assays. Our results provide evidence that at blastula stages, BMP signals inhibit the acquisition of eye-field character, but from neural tube/optic vesicle stages, BMP signals from the lens are crucial for the maintenance of eye-field character, inhibition of dorsal telencephalic cell identity and specification of neural retina cells. Subsequently, our results provide evidence that a Rax2-positive eye-field state is not sufficient for the progress to a neural retina identity, but requires BMP signals. In addition, our results argue against any essential role of Wnt or FGF signals during the specification of neural retina cells, but provide evidence that Wnt signals together with BMP activity are sufficient to induce cells of retinal pigment epithelial character. We conclude that BMP activity emanating from the lens ectoderm maintains eye-field identity, inhibits telencephalic character and induces neural retina cells. Our findings link the requirement of the lens ectoderm for neural retina specification with the molecular mechanism by which cells in the forebrain become specified as neural retina by BMP activity. © 2015. Published by The Company of Biologists Ltd.
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