Gene orchestrates creation of sight – entirely in the dark

ONE of the most remarkable aspects of the human eye is that the entire organ, built as it is for vision, is made entirely in the dark.

How such a process comes about has challenged the curiosity of scientists for generations, not least among whom was the English physiologist and 1932 Nobel laureate, Charles Sherrington. Readers of his book, Man and His Nature, marvelled at how Sherrington described how the human eye develops through a myriad of biochemical steps.

"Time after time, so perfectly is all performed that the infant eye is a good and fitting eye, and the mind soon is instructing itself and gathering knowledge through it. And the child’s eye is not only an eye true to the human type, but an eye with personal likeness to its individual parent’s," Sherrington wrote in Man and His Nature in 1940.

"The many cells which made it have executed correctly a multitudinous dance engaging millions of performers in hundreds of sequences of particular different steps, differing for each performer according to his part. To picture the complexity and the precision beggars any imagery I have. But it may help us to think further."

Thankfully, an American research team is taking Sherrington’s advice and thinking further. The team, led by Michael Myer MD St Jude Children’s Research Hospital, in Memphis, Tennessee has made some major discoveries about critical functions for a gene called ‘Prox 1’.

Published in the May issue of the journal Nature Genetics (2003;34:53-58) Dr Myer’s new research is significant because it demonstrates how the complex tissue of the retina emerges from a group of unspecialised cells known as progenitor cells.

The retina has often been referred to as "an accessible piece of the brain" in light of its origin, cellular diversity, specialiastion and processing ability. Made up of approximately 10 different cell layers, the retina consists of a heterogeneous mixture of neuronal cells, the most familiar of which are the photoreceptor rods and cones specialised for dim and bright light conditions respectively.

There are approximately 100 million rods and five million cones in the human retina. The present research report from Dr Myer’s lab focuses on how Prox 1 choreographs the "multitudinous dance engaging millions of performers" that brings about the magnus opus of the adult human retina.

The American team has shown that Prox 1 plays a critical role in stopping certain cells in the developing retina from dividing and, instead, specialising into a fully differentiated state. The cells found in the retina are among the most specialised cell types found in the body and it is the expression of the Prox 1 gene that guides this specialisation process.

Investigation of retinal cells lacking Prox 1 was shown to be less likely to stop dividing and consequently less likely to develop specialised horizontal cells. Artificial re-introduction of Prox 1 into retinal explants with an engineered virus returned the cells to their normal non-dividing state.

The research team at St Jude‘s used a variety of molecular biology techniques, including the assessment of mice lacking the Prox 1 gene. In animals without the gene, the researches found that the proper development of the "horizontal" cell layer was altered with many more unspecialised cells in abundance than would normally be expected.

The horizontal cell layer is critical in processing input signals from the primary photoreceptors and shunting these signals forward to the brain for interpretation. The entire process of horizontal cell development is tightly controlled to ensure approximately one horizontal cell for every 150 photoreceptor rod cells; any perturbation in this ratio can be readily detected.

Prox 1 has now been implicated in three central activities during embryonic development: controlling cell proliferation, directing cells to migrate to the location in the body where they are required, and helping cells specialise into the role required by the appropriate organ or tissue.

Given that the embryo develops from a single cell, there is a remarkable degree of plasticity and organisation required to build a system of approximately 100 trillion cells such as in a human. It is now becoming clear that Prox 1, a gene of just over 3,000 bases, commands a central role not only in retinal development but also in the development of the liver, the body’s lymphatic system, and even the lens.

And such development is executed to pinpoint precision in pitch black darkness!

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