Growth Factors, Diffusible Ligands, and Morphogens
Gene-expression cascades are clearly crucial for eye development, just as they are for development of most organs. However, to respond to cues in real time, cells in the developing eye require additional signals. These signals take the form of diffusible extracellular factors (termed morphogens) that are active in the earliest stages of embryonic development (see Fig 4-18).
The most important of these factors include retinoic acid (RA), Wnt, fibroblast growth factors (FGFs), the hedgehog family members Shh and Ihh, and insulin-like growth factor (IGF). These factors fall into 2 broad groups: Group 1 ligands interact with intracellular receptors that directly regulate gene expression (eg, RA). Group 2 ligands interact with cell-surface receptors that initiate an intracellular signaling cascade (eg, Wnt, FGF), often involving protein phosphorylation cascades, to eventually affect gene expression and intracellular remodeling (eg, cytoskeleton), cell motility, protein trafficking, and other processes. Defects in Wnt signaling cause familial exudative vitreoretinopathy (incomplete vascularization of the peripheral retina), leading to vitreous bleeding, tractional retinal detachments, and severe visual impairment.
Cells respond differently to ligands depending on ligand concentration in the context of a concentration gradient (also termed morphogenic gradient). In many cases, cells and tissues that have multiple potential fates utilize these diffusible ligands to activate a particular fate. For example, FGF signaling in the optic vesicle regulates expression of the basic helix-loop-helix transcription factor MITF (microphthalmia-associated transcription factor) in the optic cup, which in turn regulates the balance between development of neural retina and pigment epithelium. The interested reader is referred to several excellent reviews on the topic of eye development and diffusible ligands in embryogenesis.
Kish PE, Bohnsack BL, Gallina D, Kasprick DS, Kahana A. The eye as an organizer of craniofacial development. Genesis. 2011;49(4):222–230.
Rogers KW, Schier AF. Morphogen gradients: from generation to interpretation. Annu Rev Cell Dev Biol. 2011;27:377–407.
Sadler TW. Langman’s Medical Embryology. 13th ed. Philadelphia: Lippincott Williams & Wilkins; 2014.
Tabata T. Genetics of morphogen gradients. Nat Rev Genet. 2001;2(8):620–630.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.