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12 Looking Inside: Molecular Characterization of the Process and Its Network Extensions
4 Fast and Furious 800. The Retinal Determination Gene Network …
The study of Drosophila eye development is yielding one of the most complete
pictures of an organogenetic GRN. Already equipped with a very powerful technical toolbox, Drosophila research is ever adapting to the latest technology often
serving to benchmark them—so this research will be quickly furthering our
understanding of this network. What are the next frontiers?
Perhaps surprisingly, one of the most interesting questions still standing is the
exact roles played by the Pax6 gene ey. Neither ey nor toy, alone or jointly, seem
absolutely required for eye speciﬁcation and differentiation. Although the association between Pax6 and eyes is widespread, it is not universal. In Drosophila, the
larval eye, the small Bolwig’s organ, does not express nor requires the fly Pax6
genes, Toy or ey (Daniel et al. 1999; Suzuki and Saigo 2000), and studies in
representative species of chelicerates (Schomburg et al. 2015), planarians
(Martin-Duran et al. 2012), polychaete annelids (Arendt et al. 2002) or scyphozoan
cnidarians (Nakanishi et al. 2015) show that Pax6 genes are not expressed during
the development of their eyes. Still, in Drosophila, ey is the most powerful retinal
determination gene, in inducing ectopic eyes, both in terms of size as well as in the
number of locations. ey-induced eyes are large, while ey mutant eyes are reduced in
size, albeit this reduction is variable. Therefore, large size and Ey seem related, but
it is not clear how. One possibility is that the Ey expression domain deﬁnes the
eye-competence territory, by inducing the expression of Eya/So. Thereby, the larger
the domain, the larger the eye. This is certainly not the only thing that Ey does, as
Eya plus So generate smaller eyes than Ey does in ectopic expression assays
(Halder et al. 1995; Bonini et al. 1997; Pignoni et al. 1997; Weasner et al. 2007).
The ectodermal locations susceptible to ey-induced transformation are very speciﬁc
(Niwa et al. 2004; Salzer and Kumar 2008)—called “transformation hotspots”
(Salzer and Kumar 2008). These hotspots coincide geographically with the
so-called “transdetermination weak point”, locations in the discs prone to switch
their organ identity when disc fragments are transplanted for long periods into the
abdomen of host females, or when exposed to Wg during development (Schubiger
1971; Sustar and Schubiger 2005; Schubiger et al. 2010). The cells at these weak
points may be especially plastic. In a “Waddingtonian landscape” view
(Waddington 1957), these cells might have several developmental trajectories (or
“creodes”) almost equally accessible, at least transiently, with Wg signaling
increasing their indeterminacy. In this context, Ey might render more accessible the
eye trajectory—perhaps repressing the non-eye creodes (see also Salzer and Kumar
2010), rather than activating the eye program. In fact, expression of antennal
determinants is occasionally derepressed in ey mutant cells (Punzo et al. 2004).
Larger eye sizes can also be achieved by stimulating progenitor proliferation and by
delaying the onset of eye differentiation (thus providing for an extended proliferative period). In any case, the developmental window for Ey’s action seems to be
early, because the simultaneous attenuation of Ey and Toy (with RNAi) to undetectable levels during L2 in cell clones does not result in severe eye developmental
F. Casares and I. Almudi
defects (Lopes and Casares 2010). In any case, a better understanding of the
function of this conserved family of TFs will require the characterization of the full
set of its direct targets and their further functional characterization along eye
Related to the ability of Ey to facilitate the development of large eyes, understanding the regulation of Tsh and its function, in molecular detail, is key. The
deﬁnition of the eye ﬁeld depends on differential gene expression of Tsh in one of
the two disc layers, the one becoming the columnar main epithelium. The mechanism regulating Tsh is thus involved in establishing/limiting eye competence. The
capacity of Tsh to respecify the squamous peripodial epithelium and to change cell
morphology into cuboidal hints at a relationship between cell morphology and fate
speciﬁcation. The fact that there is a very limited knowledge on the function of Tsh
and the identity of its targets hinders progress in this direction.
If Pax6 genes favor eye competence and help producing large eyes, the partners
Eya and So seem to be the actual eye selectors. If this is indeed the case, again, to
translate “eye” in molecular terms, the full complement of Eya + So targets needs
to be identiﬁed. This collection of target genes may contain the minimal set of
genes required to specify a “generalized eye”. Testing this hypothesis is becoming
increasingly feasible by extending the application of new technologies to a larger
range of organisms at key phylogenetic positions.
Another aspect of the network that is poorly understood molecularly is the
integration of Dpp and Hh pathways. Both pathways are partially redundant in hth
regulation and cell cycle control as well as in triggering the epithelial changes that
generate the morphogenetic furrow. Yet the Dpp and Hh pathways are very little
connected—if at all. How come that their functions are redundant?
The network’s backbone is a positive feed-forward loop with an autoregulation
(between Eya and So), a motif that generally ensures a consistent output (Guantes
and Poyatos 2008). This, on its own, justiﬁes the very consistent ﬁnal output of the
developmental system: the tight activation of ato. However, up to date, all the
analyses have been generally carried out over the average of the cells, as if there
were no intercellular variation (either mean proﬁles of a single gene’s expression or
average transcriptomic proﬁles). However, biological processes are intrinsically
variable. What the degree of variability is, to what extent mechanisms to minimize
this intrinsic noise are built-in within the network (and which are their components),
or whether noise is also fueling some of the transitions, are questions that can only
be addressed through single-cell level of analysis. With such descriptions, a given
cell “state” will no longer be a vector comprising mean gene/protein expressions,
but rather vectors of probability distributions. The challenge for GRNs will be to
take a leap from describing linkages and deﬁning simple regulatory motifs to
become predictive and analytic tools for some sort of “biological statistical
mechanics” (Garcia-Ojalvo and Martinez Arias 2012).
In addition to gene regulatory motifs, gene expression is stabilized through
epigenetic modiﬁcations. In fact, mutations that affect components of the
4 Fast and Furious 800. The Retinal Determination Gene Network …
chromatin-modifying Polycomb and Trithorax complexes derail early eye development (Janody et al. 2004). However, in the case of the eye, while on the one hand
the transitional states must be stable to ensure robust eye development, they ought
to be also flexible to allow fast transitions. The speciﬁc role of chromatin modiﬁers
has still to be integrated with the action of more “conventional” TFs.
In addition, the eye GRN is highly dynamic and contingent—i.e. each step is
dependent upon the previous ones. We have presented here just a window through
this dynamics. However, the challenge is to knit the GRN starting at the inception
of the eye primordium in the embryo through to the differentiation of PRs and other
cell types. The early larval stages are poorly characterized and it is a working
assumption that L1/L2 cells are very much like the anterior progenitors in L3, but it
may be a mistake to assume that the logic in L3 (in the progenitor ﬁeld) faithfully
reflects the earlier stages. Recent efforts at deﬁning the GRN downstream of ato are
seeing great progress. However, there is a bridge to be built between the events
happening anterior to the MF (reviewed here) and posterior to it.
The eye determination GRN works in a growing tissue with precisely deﬁned
shape, that includes a constriction of the whole disc marking the separation between
antenna and eye, different cellular morphotypes, furrows and folds, all potential
causes or consequences of differential tensions. Whether physical forces are to be
included in models regulating the growth and differentiation of the eye, and how
these mechanical parameters should eventually be integrated in the gene network
are questions that need to be studied.
The Drosophila eye is an organ of exemplar constancy. However, the size (and
shape) of eyes across diptera is remarkably variable. It is very likely that these
changes have occurred by introducing developmental variations, which in one way
or another, must be connected with the early eye gene network—e.g. by varying the
speed at which the MF travels, or altering proliferation rates of progenitors. Finding
out these changes and their genetic, cellular, molecular and/or physical bases may
throw light on the understudied problem of how organ size varies during evolution.
Looking beyond diptera, comparative studies based on Drosophila research should
identify genetic kernels, common to most insects (and beyond), as well as evolutionary variations generating morphologically and functionally diverse eyes.
The works reviewed in this chapter set strong foundations for continuing efforts
in Drosophila to tackle all these fascinating questions, and more.
Acknowledgments Recent work in the Casares lab related to the subject of this review has been
partly funded through grants BFU2009-07044 and BFU2012-34324 from the Spanish Ministry of
Science and Innovation/MINECO. We specially thank S. Aerts (KU, Leuven), M. Friedrich
(Wayne State Univ., Detroit), F. Pichaud (UCL, London) and F. Pignoni (Upstate Medical Univ.,
Syracuse) for their critical comments. IA has been supported through “Programa de
Fortalecimiento” of Pablo de Olavide University and a MSC postdoctoral contract from the EU
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