The roles of intrinsic and extrinsic cues and bHLH genes in the determination of retinal cell fates

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Abstract

A fundamental issue concerning development of the vertebrate retina is the relative contributions of extrinsic and intrinsic cues to the determination of cell fate. Recent findings suggest that retinal progenitors go through a series of changes in intrinsic properties that control their competence to make different cell types and that extrinsic cues influence the ratios of the cell types that they produce. Recent studies of the role of the basic helix-loop-helix genes in retinal development have indicated that they can regulate competence and/or other aspects of cell fate determination.

Introduction

The vertebrate retina comprises six major classes of neurons and one class of glia. These cell types are produced in an orderly manner that is generally conserved (reviewed in [1]). Lineage analyses have indicated that mitotic progenitors are multipotent 2, 3, 4, 5, 6. This multipotency persists throughout development, as revealed most clearly by the smaller retrovirally marked clones initiated by infection of the postnatal rat retina [4]. Many of these clones had only two cells, and these could comprise two very different cell types (Figure 1a). How can such clones arise? Two extreme models can be proposed. In model 1 (Figure 1b), the environment is completely responsible for dictating the choice of cell fate. One type of progenitor is invoked and is responsive to an array of extrinsic cues such that several cell types can be produced. In model 2 (Figure 1c), all information concerning cell fate derives from intrinsic information. As stated above, however, lineage analyses have shown that the retina does not have committed progenitors restricted to producing only one cell type, with the possible exception of a rod progenitor. Thus, in model 2, distinct progenitors that each make more than one cell type (again, with the exception of a rod progenitor) are predicted. In this review, the issue of whether model 1 or 2 is supported by recent experiments and the role that basic helix-loop-helix (bHLH) genes play in the production of retinal cell types are addressed.

Section snippets

Extrinsic and intrinsic cues control retinal cell fate determination

During the late embryonic period in rats, ganglion cells, amacrine and horizontal interneurons, and cone and rod photoreceptors are produced (M LaVail, personal communication). At least two types of progenitor cells in the retina are present at this time [7••]. One type expresses two markers of mature horizontal and amacrine cells: the syntaxin epitope recognized by the monoclonal antibody HPC-1 and the sugar epitope recognized by the monoclonal antibody VC1.1. The cells expressing these

bHLH genes may contribute to intrinsic properties that affect cell fate choices

Candidate genes that might regulate intrinsic properties such as competence, and/or participate at other levels in the cell fate or differentiation processes, encode transcription factors, including the bHLH family. Multiple bHLH genes that are expressed in the developing retina have been isolated. These include the negative regulator Hes1 [29] and the positive regulators Mash1/Cash1 30, 31, 32, 33, neurogenin2/Math4a 34, 35, ATH3/NeuroM/Xath3 36•, 37, NeuroD 38, 39••, Math5/Xath5 40••, 41••,

Conclusions

The findings of the studies discussed above can be examined to see whether they support one of the proposed two models (see Figure 1b,c). Elements of both models appear to be correct (Figure 2). The idea of distinct types of progenitors, as suggested by model 2, is supported by recent experiments and by the heterogeneity of expression of bHLH genes among progenitors. Earlier work also supports the notion of distinct progenitor cells: a cone progenitor in the E5 chick retina [44] and a ganglion

Acknowledgements

I am grateful to the members of my laboratory for their thoughtful discussions of the data and ideas included in this review, and to Eric Morrow and Rick Livesey for their suggestions and comments on the manuscript.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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