Retinal cell fate determination and bHLH factors

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Abstract

Retinal development is controlled antagonistically by multiple basic helix–loop–helix (bHLH) transcriptional activators and repressors. bHLH repressors suppress bHLH activators and promote maintenance of progenitors and generation of glial cells. In contrast, bHLH activators override activities of bHLH repressors and promote neuronal differentiation. However, bHLH activators alone are not sufficient but homeodomain factors are additionally required for neuronal subtype specification. It is likely that homeodomain factors regulate the layer specificity but not the neuronal fate while bHLH activators determine the neuronal fate within the homedomain factor-specified layers. Thus, combinations of proper bHLH and homeodomain factors are required for neuronal subtype specification.

Introduction

During retinal development, progenitors change their competency over time under the control of extrinsic (such as neurotrophic factors) and intrinsic regulators (such as transcription factors) [1], [2], [3]. In mouse, retinal progenitors initially proliferate extensively to increase the cell number but, from embryonic day (E) 10.5 onward, proliferating progenitors start cell differentiation. In the neural retina, there are six types of neurons and one type of glial cells (Müller glial cells), which constitute three cellular layers: rod and cone photoreceptors in the outer nuclear layer (ONL), horizontal, bipolar, and amacrine interneurons and Müller glial cells in the inner nuclear layer (INL), and ganglion and displaced amacrine cells in the ganglion cell layer (GCL) (Fig. 1B). These seven types of cells are differentiated from common progenitors in an order conserved among many species: ganglion cells first and Müller glial cells last (Fig. 1A). Thus, retinal development consists of three successive processes: (i) proliferation of progenitors, (ii) neurogenesis, and (iii) gliogenesis. It has been shown that these processes are controlled by multiple basic helix–loop–helix (bHLH) genes, which function as intrinsic regulators [4], [5].

There are two functionally distinct groups of bHLH genes: repressors and activators. bHLH repressors such as Hes1 and Hes5, homologs of Drosophila hairy and Enhancer of split genes, are expressed by common progenitors and inhibit neuronal differentiation. These bHLH repressors promote maintenance of progenitors in the embryonal retina and glial differentiation in the postnatal retina. When the bHLH repressors are downregulated, then bHLH activators such as Mash1 and Math5, homologs of Drosophila proneural genes acheate-scute and atonal, promote neuronal differentiation. In this review, we discuss roles of bHLH repressors and activators in maintenance of progenitors and specification of neurons and glial cells.

Section snippets

Maintenance of progenitors by bHLH repressors

During retinal development, progenitors proliferate extensively to increase the cell number while giving rise to distinct subtypes of cells over time by changing their competency. Thus, it is essential to maintain progenitors until late stages to have not only the enough number of cells but also a full range of cell types. It has been shown that the bHLH factor Hes1 plays an essential role in maintenance of retinal progenitors. Hes1 is a transcriptional repressor that recruits the corepressor

Generation of Müller glia by bHLH repressors

In the postnatal retina, Hes1 and Hes5 expression does not disappear but is observed in differentiating Müller glial cells, the last cell fate (Fig. 1A). This expression is transient and soon disappears by postnatal day (P) 10. Misexpression of Hes1 or Hes5 in the postnatal retina promotes generation of Müller glial cells [14], [15]. Similar gliogenic activities are also reported for Notch [14], [16], [17] and the homeodomain gene rax [14]. rax is known to promote proliferation of retinal

Neuronal cell fate determination by bHLH activators

bHLH activators such as the Achaete-Scute homolog Mash1 and Atonal homologs Math3, Math5 and NeuroD are expressed initially in the ventricular zone but later by subsets of differentiating neurons (Fig. 1A). bHLH activators are known to promote the neuronal fate and inhibit the glial fate in the brain [24]. Misexpression of these bHLH activators in the developing retina also generates neurons only [25]. The precise mechanism by which bHLH activators suppress bHLH repressors during neuronal

Bipolar cell fate specification by the bHLH activators Mash1/Math3 and the homeodomain factor Chx10

Mash1 is transiently expressed by differentiating bipolar cells (Fig. 1A), and Mash1-null mutation decreases bipolar cells while increasing Müller glial cells [27]. Math3 is also expressed by bipolar cells (Fig. 1A), but Math3-null mutation does not affect bipolar cell development [27]. In contrast, in Mash1–Math3-double mutations, virtually all bipolar cells are abolished, and those that would normally differentiate into bipolar cells adopt the Müller glial cell fate (Fig. 3B(b)) [27]. Thus,

Amacrine cell fate specification by the bHLH activators NeuroD/Math3 and the homeodomain factors Pax6/Six3

The bHLH gene NeuroD is transiently expressed by differentiating amacrine cells (Fig. 1A) [30]. Although NeuroD-null mutation delays amacrine cell development, the amacrine cell number is recovered to the normal level by P12, indicating that NeuroD alone is not sufficient for amacrine cell development [30]. Similarly, although Math3 is transiently expressed by differentiating amacrine cells, Math3-null mutation does not affect amacrine cell development [27]. However, in NeuroD–Math3-double

Specification of other neuronal subtypes by bHLH and homeodomain factors

In addition to bipolar and amacrine cells, other retinal neurons have been also analyzed for dependency upon bHLH and homeodomain genes. Recent studies revealed that the bHLH activator Math5 plays an essential role in ganglion cell development. Among the bHLH activators, Math5 is expressed earlier in the ventricular zone than others. The expression starts from the boundary between the optic stalk and the neural retina, spreads circumferentially and expands throughout the neural retina [32]. It

Conclusion

The three processes of retinal development (proliferation of progenitors, neurogenesis and gliogenesis) are all controlled by bHLH genes. During these processes, progenitors are known to change their competency over time. Early progenitors have a competency to become early-born cell types such as ganglion and amacrine cells, and they adopt the ganglion cell fate when Math5 is on and the amacrine cell fate when NeuroD or Math3 is on (Fig. 4). Late progenitors have a competency to become

Acknowledgements

This work was supported by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan and Japan Society for the Promotion of Science. J.H. was supported by Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists.

References (46)

  • I. Masai et al.

    Midline signals regulate retinal neurogenesis in zebrafish

    Neuron

    (2000)
  • J.N. Kay et al.

    Retinal ganglion cell genesis requires lakritz, a zebrafish atonal homolog

    Neuron

    (2001)
  • S. Kanekar et al.

    Xath5 participates in a network of bHLH genes in the developing Xenopus retina

    Neuron

    (1997)
  • I. Ahmad

    Mash-1 is expressed during ROD photoreceptor differentiation and binds an E-box, E(opsin)-1 in the rat opsin gene

    Brain Res. Dev. Brain Res.

    (1995)
  • S. Chen et al.

    Crx, a novel Otx-like paired-homeodomain protein, binds to and transactivates photoreceptor cell-specific genes

    Neuron

    (1997)
  • C.L. Freund et al.

    Cone–rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor

    Cell

    (1997)
  • K. Tessmar et al.

    A screen for co-factors of Six3

    Mech. Dev.

    (2002)
  • F.J. Livesey et al.

    Vertebrate neural cell-fate determination: lessons from the retina

    Nat. Rev. Neurosci.

    (2001)
  • R.L. Davis et al.

    Vertebrate hairy and Enhancer of split related proteins: transcriptional repressors regulating cellular differentiation and embryonic patterning

    Oncogene

    (2001)
  • M. Ishibashi et al.

    Targeted disruption of mammalian hairy and Enhancer of split homolog-1 (HES-1) leads to up-regulation of neural helix–loop–helix factors, premature neurogenesis, and severe neural tube defects

    Genes Dev.

    (1995)
  • T. Ohtsuka et al.

    Hes1 and Hes5 as Notch effectors in mammalian neuronal differentiation

    EMBO J.

    (1999)
  • T. Honjo

    The shortest path from the surface to the nucleus: RBP-J kappa/Su(H) transcription factor

    Genes Cells

    (1996)
  • S. Artavanis-Tsakonas et al.

    Notch signaling: cell fate control and signal integration in development

    Science

    (1999)
  • Cited by (0)

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