Neurogenesis and Specification of Retinal Ganglion Cells

Across all species, retinal ganglion cells (RGCs) are the first retinal neurons generated during development, followed by the other retinal cell types.

How are retinal progenitor cells (RPCs) able to produce these cell types in a specific and timely order? 

the ciliary marginal zone is a new stem cell niche in mice contributing to retinal neurogenesis, especially to the generation of ipsilateral RGCs.

RGCs are composed of many different subtypes that are anatomically, physiologically, functionally, and molecularly defined.

Retinal ganglion cells (RGCs) are the sole output neurons from the retina and thus integrate and transmit all visual information to the brain.

How are these RGCs generated during development?

Over recent decades, much progress has been made to improve the understanding of RGC neurogenesis and differentiation. The current view is that retinal progenitor cells in vertebrates can generate different retinal types in a stochastic manner but with a probabilistic bias for some cell types that change during development. This model could explain why all retinal cell types can be generated at any given developmental time but with a different probability, ending up with RGCs generated mostly early on and rod photoreceptors later.

The extrinsic and intrinsic factors that regulate the cell fate determination are being isolated, with compelling evolutionary conserved factors initially identified in the more deterministic neurogenesis of the drosophila eye.

However, two aspects remain to be established:

(1) how the developmental expression of these factors is regulated, and

(2) how the change in cell fate probabilities occur over time.

The transcription factors that regulate RGC neurogenesis are identified: Atoh7 and Pou4f2 appear as the key regulators with several transcription factors in between.

As RGCs are not a homogeneous population, several studies have tried to identify the molecular determinants and/or markers of RGC subtypes.

This characterization was done initially by combinatorial expression of various transcription factors or markers for different types of RGCs.

However, the recent emergence of single-cell RNA sequencing technology will hopefully allow the identification of new markers for RGC subtypes but also to determine their specification pathways during development.

In the future, studies will undoubtedly link molecular specification of RGC subtypes with their brain connectivity to decipher the molecular mechanisms that are at hand.

Finally, understanding the developmental mechanisms determining the specification of retinal cells is crucial for the efficient, targeted generation of retinal cells from induced pluripotent stem cells of patients for research on the human retinal neurogenesis and also potential therapeutic strategies.