A gene regulatory hierarchy for retinal ganglion cell specification and differentiation
Introduction
Cell specification and differentiation are fundamental processes of animal development and are subject to extensive and precise regulation at the molecular level. For any specific cell type, key regulatory players, including intrinsic transcription factors and extrinsic signaling molecules, are required [1], [2], [3]. Cell specification and differentiation in the vertebrate retina have been studied extensively and significant progress has been made, particularly with the advent of gene knockout mouse models with retinal defects. The development of the vertebrate retina and the molecular mechanisms involved are highly conserved among vertebrate species. During development, the six neuronal cell types (rod and cone photoreceptors, bipolar cells, horizontal cells, amacrine cells, and retinal ganglion cells (RGCs)) and one glial cell type (Muller cells) in the mature retina all arise from the same population of retinal neuroblasts [4], [5]. Specification of these cell types follows a distinct temporal and spatial order [6], [7], [8], [9], [10]. It has been proposed that the temporally ordered birth of the different cell types is due to intrinsic changes of retinal progenitor cells over time, resulting in corresponding changes in their competence to become different cell types [4], [7]. Although how this competence change occurs is not well understood, many genes involved in the specification and differentiation of different retinal cell types have been identified [4], [5], [11]. In this review, we focus on the current understanding of the molecular regulatory events that occur during the specification and differentiation of RGCs, the earliest retinal cell type to be specified. We also discuss the technical advances that will eventually lead to a comprehensive model of the gene regulatory network for RGC specification and differentiation. We distinguish specification from differentiation not necessarily to imply well-defined transitions in cell state but rather to indicate that the starting point of RGC formation, namely an undifferentiated cell dedicated to an RGC fate, differs from the later steps of overt morphological differentiation. The terms specification, determination, and commitment are used interchangeably to indicate that a progenitor cell has become dedicated to an RGC fate. We use the term competence to define a cell (or field of cells) that has the potential to become an RGC but may follow another fate, depending on its intrinsic and extrinsic environments.
Section snippets
Lineage history of RGCs
In the mouse, RGCs first appear at embryonic day (E) 11.5, when progenitor cells exit the cell cycle and begin to express early RGC markers. Specification of RGCs starts from the center of the retina and expands anteriorly toward the periphery [6], [12], [13]. How RGC specification is initiated from a seemingly uniform population of naı̈ve retinal neuroblasts is unclear. That RGC specification starts at the center of the retina indicates that inductive cues from neighboring structures, possibly
Hierarchical gene regulatory network for RGC specification
RGC formation is a continuation of the early morphological and molecular processes of retina development. RGC specification and differentiation proceed as a stepwise process when the retina has developed to a certain stage. A specific gene regulatory program is required to accomplish each step. Thus, gene regulation during RGC formation is inherently hierarchical, with transcription factors regulating the early events positioned at the top of the hierarchy and those for the late events at the
Transcriptional regulation during RGC differentiation
Once committed to its fate, an RGC precursor undergoes terminal differentiation to become a functionally mature RGC. Like all specialized neurons, RGCs differentiate in several stages [48]. First, committed cells migrate to the innermost layer of the retinal epithelium, the future ganglion cell layer. At the same time, the cells establish their apical–basal polarity and send out axons and dendrites. The dendritic projections make connections with the amacrine, bipolar, and horizontal
Not all RGCs are the same
Mature RGCs are not a homogeneous population. Distinct RGC subtypes can be identified based on their morphology, physiological functions and axon projection patterns. RGCs vary in soma size and morphology, and there are 10–15 different RGC types in different species [48], [69]. There is considerable variability in the composition of different-sized RGCs in the retinas of mammalian species [48]. For example, based on soma size, there are three major types of RGCs in primates; parasol (the
Perspectives
Although substantial progress has been made in determining the genetic and molecular bases of RGC specification and differentiation, obtaining a comprehensive picture of the gene regulatory network driving these processes continues to be a long-term goal. Commitment to the RGC fate requires Ath5 action, but how and when in its lineage history a competent progenitor cell advances to the RGC specification pathway is unclear. Improved methods for genetic manipulation and lineage tracing are now
Acknowledgements
We thank the members of the Klein lab for helpful discussions. Our work on mouse retina development was supported by NIH–NEI grants EY11930 and EY13523 and by the Robert A. Welch Foundation.
References (95)
The roles of intrinsic and extrinsic cues and bHLH genes in the determination of retinal cell fates
Curr. Opin. Neurobiol.
(1999)- et al.
Molecular mechanisms underlying cell fate specification in the developing telencephalon
Curr. Opin. Neurobiol.
(2002) - et al.
Generating neuronal diversity in the retina: one for nearly all
Trends Neurosci.
(2002) - et al.
Cell birthdays in Xenopus laevis retina
Differentiation
(1995) - et al.
Retinal neurogenesis: the formation of the initial central patch of postmitotic cells
Dev. Biol.
(1999) - et al.
Cellular determination in the Xenopus retina is independent of lineage and birth date
Neuron
(1988) - et al.
Lineage-independent determination of cell type in the embryonic mouse retina
Neuron
(1990) - et al.
Asymmetric inheritance of radial glial fibers by cortical neurons
Neuron
(2001) - et al.
Radial glia is a progenitor of neocortical neurons in the developing cerebral cortex
Neurosci. Res.
(2001) - et al.
Pax6 is required for the multipotent state of retinal progenitor cells
Cell
(2001)
Xotch inhibits cell differentiation in the Xenopus retina
Neuron
An overview of the Notch signalling pathway
Semin. Cell Dev. Biol.
Proneural enhancement by Notch overcomes Suppressor-of-Hairless repressor function in the developing Drosophila eye
Curr. Biol.
Notch signaling can inhibit Xath5 function in the neural plate and developing retina
Mol. Cell Neurosci.
Xath5 participates in a network of bHLH genes in the developing Xenopus retina
Neuron
Retinal ganglion cell genesis requires lakritz, a zebrafish atonal homolog
Neuron
POU domain factor Brn-3b is essential for retinal ganglion cell differentiation and survival but not for initial cell fate specification
Dev. Biol.
The bHLH factors Xath5 and XNeuroD can upregulate the expression of XBrn3d, a POU-homeodomain transcription factor
Dev. Biol.
Expression of two novel mouse Iroquois homeobox genes during neurogenesis
Mech. Dev.
Expression of Irx6 during mouse morphogenesis
Mech. Dev.
A POU domain transcription factor-dependent program regulates axon pathfinding in the vertebrate visual system
Neuron
X-MyT1, a Xenopus C2HC-type zinc finger protein with a regulatory function in neuronal differentiation
Cell
Topographic mapping from the retina to the midbrain is controlled by relative but not absolute levels of EphA receptor signaling
Cell
Expression and activation of STAT proteins during mouse retina development
Exp. Eye Res.
Abnormal polarization and axon outgrowth in retinal ganglion cells lacking the POU-domain transcription factor Brn-3b
Mol. Cell Neurosci.
Autoregulation of neurogenesis by GDF11
Neuron
Regulation of axial patterning of the retina and its topographic mapping in the brain
Curr. Opin. Neurobiol.
Misexpression of the Emx-related homeobox genes cVax and mVax2 ventralizes the retina and perturbs the retinotectal map
Neuron
Mammalian RNAi for the masses
Trends Genet.
Conserved noncoding sequences are reliable guides to regulatory elements
Trends Genet.
Mapping chromosomal proteins in vivo by formaldehyde-crosslinked-chromatin immunoprecipitation
Trends Biochem. Sci.
Transcriptional codes and the control of neuronal identity
Annu. Rev. Neurosci.
Vertebrate neural cell-fate determination: lessons from the retina
Nat. Rev. Neurosci.
Cell differentiation in the retina of the mouse
Anat. Rec.
Cell fate determination in the vertebrate retina
Proc. Natl. Acad. Sci. U.S.A.
Cytogenesis in the monkey retina
J. Comp. Neurol.
Rods and cones in the mouse retina. II. Autoradiographic analysis of cell generation using tritiated thymidine
J. Comp. Neurol.
Molecular aspects of vertebrate retinal development
Mol. Neurobiol.
Patterning of the zebrafish retina by a wave of sonic hedgehog activity
Science
A common progenitor for neurons and glia persists in rat retina late in development
Nature
Multipotent precursors can give rise to all major cell types of the frog retina
Science
Math5 encodes a murine basic helix–loop–helix transcription factor expressed during early stages of retinal neurogenesis
Development
BETA2/NeuroD1 null mice: a new model for transcription factor-dependent photoreceptor degeneration
J. Neurosci.
p27Kip1 and p57Kip2 regulate proliferation in distinct retinal progenitor cell populations
J. Neurosci.
Vertebrate retinal ganglion cells are selected from competent progenitors by the action of Notch
Development
Extrinsic and intrinsic factors control the genesis of amacrine and cone cells in the rat retina
Development
Late retinal progenitor cells show intrinsic limitations in the production of cell types and the kinetics of opsin synthesis
J. Neurosci.
Cited by (96)
Congenital aniridia beyond black eyes: From phenotype and novel genetic mechanisms to innovative therapeutic approaches
2023, Progress in Retinal and Eye ResearchStem cell therapies for glaucoma and optic neuropathy
2021, Recent Advances in iPSCs for Therapy, Volume 3: A Volume in Advances in Stem Cell BiologySpecification of retinal cell types
2020, Patterning and Cell Type Specification in the Developing CNS and PNS: Comprehensive Developmental Neuroscience, Second EditionTowards stem cell-based neuronal regeneration for glaucoma
2020, Progress in Brain ResearchSox11 Expression Promotes Regeneration of Some Retinal Ganglion Cell Types but Kills Others
2017, NeuronCitation Excerpt :Together, our results indicate that Pten deletion could further enhance axonal regeneration from non-α-RGCs induced by Sox11 overexpression. Multiple factors have been shown to be key in the differentiation of RGCs during development (Livesey and Cepko, 2001; Mu and Klein, 2004). However, it remains unclear which factors are most relevant to the axon growth program.