Trends in Neurosciences
Volume 25, Issue 1, 1 January 2002, Pages 32-38
Journal home page for Trends in Neurosciences

Review
Generating neuronal diversity in the retina: one for nearly all

https://doi.org/10.1016/S0166-2236(00)02028-2Get rights and content

Abstract

Visual perception of our environment essentially depends on the correct assembly of seven principal cell types into the functional architecture of the neuroretina. During retinogenesis these cell types derive from a common population of multipotent retinal progenitor cells (RPCs) residing in the inner layer of the optic cup. In contrast to other well studied regions of the developing CNS, retinal cell diversification is apparently not achieved by spatial prepatterning into distinct progenitor domains, but rather by the sequential production of cell types in a defined histogenetic order. Several lines of evidence suggest that this observation reflects substantial intrinsic changes in the retinogenic potential of RPCs. Recent advances, however, point at the existence of a common molecular framework underlying the retinogenic potential of RPCs throughout retinal neurogenesis.

Section snippets

Cellular diversification in the developing retina: extrinsic versus intrinsic cues

Cell lineage tracing in mammals and amphibia revealed that RPCs are multipotent and retain their ability to generate different cell types up to the final cell division 4, 5, 6. For the embryonic Xenopus retina these experiments unveiled a complete lineage-independence of retinal cell fate choice among the progeny of single labeled RPCs 5, 6. After retroviral tracing of RPCs in the postnatal mammalian retina, a substantial portion of labeled clones consisted of two or more different cell types,

Complexity of the retinal progenitor cell pool

Another issue which has to be taken into account when interpreting these findings is the heterogeneity of the RPCs pool during retinogenesis, with the apparent coexistence of non-overlapping RPC subpopulations with distinct preferences for the range of cell types generated [9]. One such lineage-restricted RPC population that preferentially gave rise to amacrine cells and, later, photoreceptor cells, was identified on the basis of selective expression of particular epitopes [19].

A set of

Pax6 at the link between early eye development and retinal cell fate determination

In all vertebrate species analyzed so far, a similar set of pivotal transcription factors, most prominently Pax6, Rx1, Six3/6 and Lhx2, which act in initiating vertebrate eye development, continues to be present during the ensuing steps of retinal neurogenesis (Fig. 4b) 41, 42, 43, 44, 45, 46, 47. In the developing mouse retina, Pax6 is expressed in virtually all mitotic RPCs during all stages of retinogenesis, including postnatal stages shortly before the last retinal cells become postmitotic (

Retinogenic bHLH transcription factors at the link between Pax6 and retinal cell fate determination

How does Pax6 operate in mediating the retinogenic potential of RPCs? The bHLH factors Ngn2, Mash1 and Math5 all fail to be activated in Pax6 deficient RPCs (Fig. 3) [33]. Moreover, these factors appear to constitute direct targets of Pax6 mediated transcriptional activation 22, 33, 53. Pax6 might control the availability of the full range of cell fates to RPCs essentially by mediating the activation of such retinogenic transcription factors (Fig. 2, Fig. 3).

Another retinogenic bHLH factor,

From multipotency to lineage-restriction

To explain the observed Pax6 dependent activation of bHLH factors in particular subsets of RPCs, in an otherwise homogeneously Pax6? RPC pool, the most parsimonious interpretation has been that these findings reflect a transition from an uncommitted (possibly stem-cell-like) towards a lineage-restricted RPC state [33]. In this respect the Pax6? population defines the most ‘primitive’ and the bHLH?Pax6? population demarcates the lineage-restricted state (Fig. 2).

This situation would be analogous

Some unresolved issues

An important issue which remains unclear concerns the precise lineage relationships between biased RPC subpopulations. In particular it has to be elucidated how fixed or plastic the restrictions towards particular cell fates are for certain molecularly definable RPC subpopulations. Furthermore, it remains unclear how the action of secreted instructive factors such as Shh or TGF-α are linked to the expression of retinogenic factors like Math5 or NeuroD in subsets of RPCs. In this respect,

Acknowledgements

We thank the members of the P.G. and Michael Kessel laboratories for support and helpful discussions. We are particularly grateful to Anastassia Stoykova, Nicole Andrejewski and Ruth Ashery-Padan for discussions and critical reading of the manuscript. The studies from which this review is derived were supported by an EU grant (B104-CT96-0042) and by the Max-Planck-Gesellschaft.

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