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12 Looking Inside: Molecular Characterization of the Process and Its Network Extensions

12 Looking Inside: Molecular Characterization of the Process and Its Network Extensions

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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

H2020 Program.


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