Eye morphogenesis driven by epithelial flow into the optic cup facilitated by modulation of bone morphogenetic protein

Significance Statement

Morphogenesis through Flowing Tissue

In an in vivo analysis of eye development, researchers at Heidelberg University and the University of Freiburg have gained fundamental new insight into the development of coloboma of the eye, prompting them to revise the classical view of the development of this sensory organ in vertebrates. By the use of in vivo 4D microscopy it was demonstrated that directed tissue flow transforms the optic vesicle into the optic cup during eye development. This is not only critical for understanding the cause of coloboma, but also means that eye development in vertebrates, including humans, is fundamentally different to what has been taught for more than 70 years. The eye is an outgrowth of the brain and forms in the embryo from a sac-like vesicle that quickly transforms into an optic cup with an interior retina surrounded on the outside by a pigmented epithelium.  Until now, the optic cup was believed to develop rather statically from the two layers of the optic vesicle, with the lens-facing layer becoming the retina and the other, lens-averted layer forming the pigmented epithelium. However in the detailed investigation of this developmental step using in vivo time-lapse microscopy in fish, it was shown, that the optic cup forms from a dynamic flow of lens averted cells into the lens facing optic cup, exactly the opposite of a static development. The researchers also found that signaling of the growth factor BMP must be modulated for the tissue to flow and transform the vesicle into the cup. Without this modulation, the tissue remains stuck on the lens-averted side and begins to develop into the retina in the wrong domain.

The researchers made several fundamental discoveries in the process:

  • Eye organogenesis is driven by a dynamic flow of tissue rather than by static development (reservoir of neuroretinal tissue in the lens averted domain of the optic vesicle).
  • The optic fissure is established by this dynamic flow.
  • This dynamic flow is regulated by BMP signaling (guarded by BMP antagonism, too much BMP signaling arrests the flow).
  • Arrested flow impairs optic fissure development and most importantly optic fissure closure, resulting in coloboma.
  • Arrested flow also results in ectopic neuroretina
  • The neuroretinal flow is bilateral (nasal and temporal) dorsal pole and ventral domain are established secondarily
  • Retinal stem cell origin was tracked back to two distinct domains in the optic vesicle


PD Dr. Stephan Heermann, Prof. Dr. J. Wittbrodt Centre for Organismal Studies

Tel.: +49 6221 54-8687 (Heermann), -6499 (Wittbrodt) [email protected], [email protected]

figure legend:

The figure shows two stages of eye development, the optic vesicle

(top) and the optic cup (below). Cells of the future stem cell domain are individually tracked (trajectories, left column) and their domains within the optic vesicle and optic cup are highlighted (right column).

The figure shows a dorsal view and represents a virtual longitudinal section. Arrows indicate the direction of stem cell flow followed in vivo over time.

Eye morphogenesis driven by epithelial flow into the optic cup facilitated by modulation of bone morphogenetic protein

Journal Reference

Heermann S1, Schütz L1, Lemke S1, Krieglstein K2, Wittbrodt J1. Elife. 2015 Feb 24;4. DOI: 10.7554/eLife.05216.001

[expand title=”Show Affiliations”]

1Centre for Organismal Studies Heidelberg, Ruprecht Karls Universität, Heidelberg, Germany.

2Department of Molecular Embryology, Institute of Anatomy and Cell Biology, University Freiburg, Freiburg, Germany.



The hemispheric, bi-layered optic cup forms from an oval optic vesicle during early vertebrate eye development through major morphological transformations. The overall basal surface, facing the developing lens, is increasing, while, at the same time, the space basally occupied by individual cells is decreasing. This cannot be explained by the classical view of eye development. Using zebrafish (Danio rerio) as a model, we show that the lens-averted epithelium functions as a reservoir that contributes to the growing neuroretina through epithelial flow around the distal rims of the optic cup. We propose that this flow couples morphogenesis and retinal determination. Our 4D data indicate that future stem cells flow from their origin in the lens-averted domain of the optic vesicle to their destination in the ciliary marginal zone. BMP-mediated inhibition of the flow results in ectopic neuroretina in the RPE domain. Ultimately the ventral fissure fails to close resulting in coloboma.

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