Size matters: The contribution of cell proliferation to the progression of the specification Drosophila eye gene regulatory network

Organ development is a complex process in which the activity of scores of interacting transcription factors and signaling pathways need to be integrated with proliferative growth. Developmental gene regulatory networks (GRNs) allow capturing essential regulatory pathways at a systems-level and provide an effective way of approaching such complexity. However typical GRNs studies focus on very early embryonic stages (usually pre-gastrulation) or late stages, when there is little or no cell proliferation, and therefore do not consider how organ growth is integrated in the developmental process. This can be conveniently investigated in the Drosophila melanogaster eye primordium.Here we present a working model meant to illustrate how during a critical period, the second larval stage, changes in cells' proliferative pattern are coordinated with the initiation of the Retinal Determination (RD) gene program. Such changes are regulated in response to two different sources of signal (Wnt1/wg and BMP2/4/dpp) produced by the anterior and posterior ends of the primordium, respectively. The dpp signaling is necessary to trigger the RD program. However in order for it to be effective, cells receiving Dpp have to be out of the wg signaling range. This is obtained thanks to the proliferative growth that precedes the onset of RD expression. With this network model many of the gene regulatory steps previously known to participate in growth and patterning are linked. Analysis of the model highlights a few essential regulatory principles, as well as poses new questions. In addition, these principles might operate during the growth and patterning of other organs.